ES2317688T3 - PPAR-GAMMA MODULATORS. - Google Patents
PPAR-GAMMA MODULATORS. Download PDFInfo
- Publication number
- ES2317688T3 ES2317688T3 ES99901492T ES99901492T ES2317688T3 ES 2317688 T3 ES2317688 T3 ES 2317688T3 ES 99901492 T ES99901492 T ES 99901492T ES 99901492 T ES99901492 T ES 99901492T ES 2317688 T3 ES2317688 T3 ES 2317688T3
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- Prior art keywords
- compound
- alkyl
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- Prior art date
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- Expired - Lifetime
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- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- -1 5-chloro-3-pyridyloxy Chemical group 0.000 claims abstract description 101
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 48
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 14
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 8
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Un compuesto que tiene la fórmula ** ver fórmula** donde -X-Ar1 es -O-piridilo, Y es -N(R12)-S(O)m- donde R 12 es hidrógeno o alquilo C 1-C 10; y el subíndice m es un número entero de 0 a 2; R 1 es alquilo C1-C10, haloalquilo C1-C10, -C(O)R 14 , -CO2R 14 o -C(O)NR 15 R 16 , R 14 es hidrógeno o alquilo C 1-C 10; R 15 y R 16 son cada uno independientemente hidrógeno o alquilo C1-C10; R 2 es fenilo sustituido opcionalmente con uno a tres sustituyentes seleccionados independientemente entre halógeno, -OCF3, -OH, -O-alquilo C1-C8, -C(O)-alquilo C1-C8, -CN, -CF3, -alquilo C1-C8 y NH2 con la condición de que cuando Ar 1 -X- es 5-cloro-3-piridiloxi, R 1 es carboetoxi e Y es -NHSO 2- y los grupos Ar 1 -X-, R 1 y -Y-R 2 ocupan posiciones en los carbonos 2, 1 y 5 del anillo de benceno, respectivamente, R 2 es distinto de 4tolilo o 2,4-dicloro-5-metilfenilo.A compound having the formula ** see formula ** where -X-Ar1 is -O-pyridyl, Y is -N (R12) -S (O) m- where R 12 is hydrogen or C 1 -C 10 alkyl; and the subscript m is an integer from 0 to 2; R 1 is C1-C10 alkyl, C1-C10 haloalkyl, -C (O) R 14, -CO2R 14 or -C (O) NR 15 R 16, R 14 is hydrogen or C 1 -C 10 alkyl; R 15 and R 16 are each independently hydrogen or C1-C10 alkyl; R 2 is phenyl optionally substituted with one to three substituents independently selected from halogen, -OCF3, -OH, -O-C1-C8 alkyl, -C (O) -C1-C8 alkyl, -CN, -CF3, -C1 alkyl -C8 and NH2 with the proviso that when Ar 1 -X- is 5-chloro-3-pyridyloxy, R 1 is carboethoxy and Y is -NHSO 2- and the groups Ar 1 -X-, R 1 and -YR 2 occupy positions at carbons 2, 1 and 5 of the benzene ring, respectively, R 2 is different from 4-tolyl or 2,4-dichloro-5-methylphenyl.
Description
Moduladores PPAR-\gamma.PPAR-? Modulators.
La presente invención se refiere a compuestos que modulan el receptor PPAR\gamma y son útiles en la diagnosis y el tratamiento de la diabetes de tipo II (y sus complicaciones) y los trastornos inflamatorios.The present invention relates to compounds which modulate the PPARγ receptor and are useful in the diagnosis and the treatment of type II diabetes (and its complications) and inflammatory disorders
Los receptores activados por proliferadores de peroxisomas (PPAR) son proteínas transductoras pertenecientes a la superfamilia de receptores de esteroides/hormonas tiroideas/retinoides. Los PPAR se identificaron originalmente como receptores de orfano, sin ligandos conocidos, pero se nombraron por su capacidad para mediar los efectos pleiotrópicos de los proliferadores de peroxisomas para ácidos grasos. Estos receptores funcionan como factores de transcripción regulados por ligandos que controlan la expresión de genes diana uniéndose a su secuencia de ADN sensible en forma de heterodímeros con RXR. Los genes diana codifican enzimas implicadas en el metabolismo de lípidos y la diferenciación de adipocitos. Por lo tanto, el descubrimiento de los factores de transcripción implicados en el control del metabolismo de lípidos ha proporcionado una nueva percepción en la regulación de la homeostasis energética en vertebrados, y ha proporcionado adicionalmente dianas para el desarrollo de agentes terapéuticos para trastornos tales como la obesidad, la diabetes y la dislipidemia.Receptors activated by proliferators of peroxisomes (PPAR) are transducer proteins belonging to the steroid / hormone receptor superfamily Thyroid / retinoids. PPARs were originally identified as Orphan receptors, without known ligands, but were named by its ability to mediate the pleiotropic effects of peroxisome proliferators for fatty acids. These receivers function as transcription factors regulated by ligands that control the expression of target genes by joining their sequence of Sensitive DNA in the form of heterodimers with RXR. Target genes encode enzymes involved in lipid metabolism and the adipocyte differentiation. Therefore, the discovery of transcription factors involved in metabolic control of lipids has provided a new perception in regulation of energy homeostasis in vertebrates, and has provided additionally targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia
El PPAR\gamma es un miembro de la superfamilia de receptores nucleares de factores de transcripción activados por ligandos y se ha demostrado que es expresado de una manera específica del tejido adiposo. Su expresión es inducida pronto durante el curso de la diferenciación de algunas líneas celulares de preadipocitos. La investigación adicional ha demostrado ahora que PPAR\gamma juega un papel fundamental en la cascada de señalización adipogénica. El PPAR\gamma también regula el gen de la ob/leptina que está implicado en la regulación de la homeostasis energética, y la diferenciación de adipocitos que se ha demostrado que es una etapa crítica a localizar contra la obesidad y las condiciones diabéticas.PPARγ is a member of the superfamily of nuclear receptors of transcription factors activated by ligands and has been shown to be expressed in a way adipose tissue specific. His expression is induced soon during the course of the differentiation of some cell lines of preadipocytes Additional research has now shown that PPAR? Plays a fundamental role in the cascade of adipogenic signaling. PPARγ also regulates the gene of the ob / leptin that is involved in the regulation of homeostasis energy, and adipocyte differentiation that has been demonstrated which is a critical stage to locate against obesity and diabetic conditions
En un esfuerzo para entender el papel de PPAR\gamma en la diferenciación de los adipocitos, algunos investigadores se han centrado en la identificación de activadores de PPAR\gamma. También se demostró que una clase de compuestos, las tiazolidinodionas, que fueron conocidas por tener efectos adipogénicos sobre las células troncales preadipocíticas y mesenquimáticas in vitro, y efectos antidiabéticos en modelos animales de diabetes mellitus no insulinodependiente (NIDDM) eran ligandos selectivos de PPAR\gamma. Más recientemente, se demostró que los compuestos que activan selectivamente PPAR\gamma murino poseen actividad antidiabética in vivo en ratones.In an effort to understand the role of PPARγ in adipocyte differentiation, some researchers have focused on the identification of PPARγ activators. It was also shown that one class of compounds, thiazolidinediones, which were known to have adipogenic effects on preadipocytic and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were selective PPAR? . More recently, it was shown that compounds that selectively activate murine PPARγ possess antidiabetic activity in vivo in mice.
A pesar de los avances realizados con los agentes antidiabéticos de la clase de la tiazolidinodiona, efectos secundarios inaceptables han limitado su uso clínico. Por lo tanto, persiste la necesidad de activadores selectivos, potentes, de PPAR\gamma que serán útiles para el tratamiento de la NIDDM y otros trastornos relacionados con el metabolismo de lípidos y la homeostasis energética. Aún más, los compuestos que bloquean la actividad PPAR\gamma serían útiles para interrumpir la maduración de los preadipocitos a adipocitos y de este modo serían útiles para el tratamiento de la obesidad y los trastornos relacionados asociados con la maduración no deseable de los adipocitos. Sorprendentemente, la presente invención proporciona compuestos que son útiles como activadores y también como antagonistas de la actividad PPAR\gamma y composiciones que los contienen.Despite the progress made with the antidiabetic agents of the thiazolidinedione class, effects Unacceptable side effects have limited clinical use. Thus, the need for selective, powerful activators of PPARγ that will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and Energy homeostasis Even more, the compounds that block the PPARγ activity would be useful to interrupt ripening from preadipocytes to adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable maturation of adipocytes. Surprisingly, the present invention provides compounds that they are useful as activators and also as antagonists of PPARγ activity and compositions containing them.
La presente invención proporciona un compuesto que tiene la fórmula:The present invention provides a compound which has the formula:
dondewhere
-X-Ar^{1} es -O-piridilo;-X-Ar1 is -O-pyridyl;
Y es -N(R^{12})-S(O)_{m}-And it is -N (R 12) - S (O) m -
dondewhere
R^{12} es hidrógeno o alquilo C_{1}-C_{10}; y el subíndice m es un número entero de 0 a 2;R 12 is hydrogen or alkyl C 1 -C 10; and the subscript m is a number integer from 0 to 2;
R^{1} es alquilo C_{1}-C_{10}, haloalquilo C_{1}-C_{10}, -C(O)R^{14}, -CO_{2}R^{14} o -C(O)NR^{15}R^{16},R1 is alkyl C 1 -C 10, haloalkyl C 1 -C 10, -C (O) R 14, -CO 2 R 14 or -C (O) NR 15 R 16,
dondewhere
R^{14} es hidrógeno o alquilo C_{1}-C_{10};R 14 is hydrogen or alkyl C 1 -C 10;
R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10};R 15 and R 16 are each independently hydrogen or alkyl C 1 -C 10;
R^{2} es fenilo para modular una condición asociada con un trastorno metabólico o inflamatorio en un anfitrión.R2 is phenyl to modulate a condition associated with a metabolic or inflammatory disorder in a host.
La presente invención también proporciona un compuesto que tiene la fórmula:The present invention also provides a compound that has the formula:
dondewhere
-X-Ar^{1} es -O-piridilo;-X-Ar1 is -O-pyridyl;
Y es -N(R^{12})-S(O)_{m}-And it is -N (R 12) - S (O) m -
dondewhere
R^{12} es hidrógeno o alquilo C_{1}-C_{10}; y el subíndice m es un número entero de 0 a 2;R 12 is hydrogen or alkyl C 1 -C 10; and the subscript m is a number integer from 0 to 2;
R^{1} es alquilo C_{1}-C_{10}, C_{1}-C_{10} haloalquilo -C(O)R^{14}, -CO_{2}R^{14} o -C(O)NR^{15}R^{16},R1 is alkyl C_ {1} -C_ {10}, C_ {-} {C} { haloalkyl -C (O) R 14, -CO 2 R 14 or -C (O) NR 15 R 16,
dondewhere
R^{14} es hidrógeno o alquilo C_{1}-C_{10};R 14 is hydrogen or alkyl C 1 -C 10;
R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10};R 15 and R 16 are each independently hydrogen or alkyl C 1 -C 10;
R^{2} es fenilo sustituido opcionalmente con uno a tres sustituyentes seleccionados independientemente entre halógeno, -OCF_{3}, -OH, -O-alquilo C_{1}-C_{8}, -C(O)-alquilo C_{1}-C_{8}, -CN, -CF_{3}, -alquilo C_{1}-C_{8} y NH_{2} con la condición de que cuando Ar^{1}-X- es 5-cloro-3-piridiloxi, R^{1} es carboetoxi e Y es -NHSO_{2}- y los grupos Ar'-X-, R^{1} y -Y-R^{2} ocupan posiciones en los carbonos 2, 1 y 5 del anillo de benceno, respectivamente, R^{2} es distinto de 4-tolilo o 2,4-dicloro-5-metilfenilo.R 2 is phenyl optionally substituted with one to three substituents independently selected from halogen, -OCF3, -OH, -O-alkyl C_ {1} -C_ {8}, -C (O) -alkyl C 1 -C 8, -CN, -CF 3, -alkyl C 1 -C 8 and NH 2 with the proviso that when Ar1 -X- is 5-chloro-3-pyridyloxy, R 1 is carboethoxy and Y is -NHSO 2 - and the groups Ar'-X-, R1 and -Y-R2 occupy carbon positions 2, 1 and 5 of the benzene ring, respectively, R2 is other than 4-tolyl or 2,4-dichloro-5-methylphenyl.
En otro aspecto, la presente invención proporciona composiciones farmacéuticas que contienen los compuestos descritos antes.In another aspect, the present invention provides pharmaceutical compositions containing the compounds described above.
Las Figuras 1-4 proporcionan estructuras para una variedad de compuestos.Figures 1-4 provide structures for a variety of compounds.
En la presente memoria se utilizan las siguientes abreviaturas: PPAR\gamma: receptor \gamma activado por proliferadores de peroxisomas; NIDDM: diabetes mellitus no insulinodependiente; Et_{3}N: trietilamina; MeOH: metanol; y DMSO: dimetilsulfóxido.In this report the following abbreviations: PPAR γ: activated γ receptor by peroxisome proliferators; NIDDM: diabetes mellitus no insulin dependent; Et 3 N: triethylamine; MeOH: methanol; Y DMSO: dimethylsulfoxide.
El término "alquilo", por sí mismo o como
parte de otro sustituyente, significa, a no ser que se indique lo
contrario, un radical hidrocarbonado de cadena lineal o ramificada o
cíclico, o una combinación del mismo, que puede estar completamente
saturado, mono- o poliinsaturado y puede incluir radicales di- y
multi- valentes, que tienen el número de carbonos designado (es
decir C_{1}-C_{10} significa de uno a diez
carbonos). Los ejemplos de los radicales hidrocarbonados saturados
incluyen grupos tales como metilo, etilo, n-propilo,
isopropilo, n-butilo, t-butilo,
isobutilo, sec-butilo, ciclohexilo,
(ciclohexil)metilo, ciclopropilmetilo, los homólogos e
isómeros de, por ejemplo, n-pentilo,
n-hexilo, n-heptilo,
n-octilo, y similares. Un grupo alquilo insaturado
es el que tiene uno o más enlaces dobles o enlaces triples. Los
ejemplos de los grupos alquilo insaturados incluyen vinilo,
2-propenilo, crotilo,
2-isopentenilo, 2-(butadienilo),
2,4-pentadienilo,
3-(1,4-pentadienilo), etinilo, 1- y
3-propinilo, 3-butinilo, y los
homólogos e isómeros superiores. También se pretende que el término
"alquilo" a no ser que se observe lo contrario, incluya
aquellos derivados de alquilo definidos con más detalle más abajo
como "heteroalquilo", "cicloalquilo" y "alquileno".
El término "alquileno" por sí mismo o como parte de otro
sustituyente significa un radical divalente derivado de un alcano,
como se ilustra mediante -CH_{2}CH_{2}CH_{2}CH_{2}-.
Típicamente, un grupo alquilo tendrá de 1 a 24 átomos de carbono,
prefiriéndose en la presente invención aquellos grupos que tienen
10 átomos de carbono o menos. Un grupo "alquilo inferior" o
"alquileno inferior" es un grupo alquilo o alquileno de cadena
corta, que tiene generalmente ocho átomos de carbono o
menos.The term "alkyl", by itself or as part of another substituent, means, unless otherwise indicated, a linear or branched or cyclic hydrocarbon radical, or a combination thereof, which may be completely saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the designated number of carbons (ie C 1 -C 10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one that has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl , 3-butynyl, and the higher homologs and isomers. It is also intended that the term "alkyl" unless otherwise noted, includes those alkyl derivatives defined in more detail below as "heteroalkyl", "cycloalkyl" and "alkylene". The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as illustrated by -CH 2 CH 2 CH 2 CH 2 -. Typically, an alkyl group will have 1 to 24 carbon atoms, those groups having 10 carbon atoms or less being preferred in the present invention. A "lower alkyl" or "lower alkylene" group is a short chain alkyl or alkylene group, which generally has eight carbon atoms or
less.
El término "heteroalquilo", por sí mismo o
combinado con otro término, significa, a no ser que se indique lo
contrario, un radical hidrocarbonado de cadena lineal o ramificada,
o cíclico estable, o sus combinaciones, que consiste en el número
de átomos establecido y de uno a tres heteroátomos seleccionados del
grupo que consiste en O, N, Si y S, y donde los átomos de nitrógeno
y azufre pueden estar oxidados opcionalmente y el heteroátomo de
nitrógeno puede estar cuaternarizado opcionalmente. El o los
heteroátomos O, N y S se pueden colocar en cualquier posición
interior del grupo heteroalquilo. El heteroátomo de Si se puede
colocar en cualquier posición del grupo heteroalquilo, incluyendo
la posición a la que está anclado el grupo alquilo al resto de la
molécula. Los ejemplos incluyen
-CH_{2}-CH_{2}-O-CH_{3},
-CH_{2}-CH_{2}-NH-CH_{3},
-CH_{2}-CH_{2}-N(CH_{3})-CH_{3},
-CH_{2}-S-CH_{2}-CH_{3},
-CH_{2}-CH_{2}-S(O)-CH_{3},
-CH_{2}-
CH_{2}-S(O)_{2}-CH_{3},
-CH=CH-O-CH_{3},
-Si(CH_{3}),
-CH_{2}-CH=N-OCH_{3}, y
-CH=CH-N(CH_{3})-CH_{3}.
Pueden estar consecutivos hasta dos heteroátomos, tal como, por
ejemplo, -CH_{2}-NH-OCH_{3} y
-CH_{2}-O-Si(CH_{3})_{3}.
También están incluidos en el término "heteroalquilo" los
radicales descritos con más detalle más abajo como
"heteroalquileno" y "heterocicloalquilo". El término
"heteroalquileno" por sí mismo o como parte de otro
sustituyente significa un radical divalente derivado de
heteroalquilo, como se ilustra mediante
-CH_{2}-CH_{2}-S-CH_{2}CH_{2}-
y
-CH_{2}-S-CH_{2}-CH_{2}-NH-CH_{2}-.
Para los grupos heteroalquileno, los heteroátomos también pueden
ocupar cualquiera o ambos extremos de la cadena. Aún más, para los
grupos conectores alquileno y heteroalquileno, no está implicada la
orientación del grupo conector.The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise indicated, a straight or branched chain hydrocarbon radical, or stable cyclic, or combinations thereof, which consists of the number of atoms established and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternarized. The heteroatom (s) O, N and S may be placed in any interior position of the heteroalkyl group. The Si heteroatom can be placed in any position of the heteroalkyl group, including the position to which the alkyl group is anchored to the rest of the molecule. Examples include
-CH 2 -CH 2 -O-CH 3, -CH 2 -CH 2 -NH-CH 3, -CH 2 -CH 2 -N (CH_ {3} - CH 3, -CH 2 -S-CH 2 -CH 3, -CH 2 -CH 2 -S (O) -CH 3, - CH 2 -
CH 2 -S (O) 2 -CH 3, -CH = CH-O-CH 3, -Yes (CH 3), -CH 2 -CH = N- OCH 3, and -CH = CH-N (CH 3) - CH 3. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si (CH 3) 3. Also included in the term "heteroalkyl" are the radicals described in more detail below as "heteroalkylene" and "heterocycloalkyl." The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as illustrated by -CH 2 -CH 2 -S-CH 2 CH 2 - and - CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. For heteroalkylene groups, heteroatoms can also occupy either or both ends of the chain. Moreover, for the alkylene and heteroalkylene linker groups, the orientation of the linker group is not involved.
Los términos "cicloalquilo" y "heterocicloalquilo", por sí mismos o combinados con otros términos, representas, a no ser que se indique lo contrario, versiones cíclicas de "alquilo" y "heteroalquilo", respectivamente. Adicionalmente, para heterocicloalquilo, un heteroátomo puede ocupar la posición a la que el heterociclo se une al resto de la molécula. Los ejemplos de cicloalquilo incluyen ciclopentilo, ciclohexilo, 1-ciclohexenilo, 3-ciclohexenilo, cicloheptilo, y similares. Los ejemplos de heterocicloalquilo incluyen 1-(1,2,5,6-tetrahidropiridil), 1-piperidinilo, 2-piperidinilo, 3-piperidinilo, 4-morfolinilo, 3-morfolinyt, tetrahidrofuran-2-ilo, tetrahidrofuran-3-ilo, tetrahidrotien-2-ilo, tetrahidrotien-3-ilo, 1-piperazinilo, 2-piperazinilo, y similares.The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with others terms, you represent, unless otherwise indicated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position to which the heterocycle binds to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. The Examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morfolinyt, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and Similar.
Los términos "halo" o "halógeno", por sí mismos o como parte de otro sustituyente, significan, a no ser que se indique lo contrario, un átomo de flúor, cloro, bromo, o yodo. Adicionalmente, se pretende que términos tales como "fluoroalquilo", incluyan monofluoroalquilo y polifluoroalquilo.The terms "halo" or "halogen", for themselves or as part of another substituent, they mean, unless otherwise indicated, an atom of fluorine, chlorine, bromine, or iodine. Additionally, it is intended that terms such as "fluoroalkyl", include monofluoroalkyl and polyfluoroalkyl.
El término "arilo", empleado solo combinado con otros términos (p. ej., ariloxi, ariltioxi, arilalquil) significa, a no ser que se indique lo contrario, un sustituyente aromático que puede ser un anillo sencillo o anillos múltiples (hasta tres anillos) que están fusionados entre sí o unidos covalentemente. Los anillos pueden contener cada uno de cero a cuatro heteroátomos seleccionados entre N, O, y S, donde los átomos de nitrógeno y azufre están oxidados opcionalmente, y los átomos de nitrógeno están cuaternarizados opcionalmente. Los grupos arilo que contienen heteroátomos pueden ser referidos como "heteroarilo" y pueden estar anclados al resto de la molécula a través de un heteroátomo. Los ejemplos no limitantes de los grupos arilo incluyen fenilo, 1-naftilo, 2-naftilo, 4-bifenilo, 1-pirrolilo, 2-pirrolilo, 3-pirrolilo, 3-pirazolilo, 2-imidazolilo, 4-imidazolilo, pirazinilo, 2-oxazolilo, 4-oxazolilo, 2-fenil-4-oxazolilo, 5-oxazolilo, 3-isoxazolilo, 4-isoxazolilo, 5-isoxazolilo, 2-tiazolilo, 4-tiazolilo, 5-tiazolilo, 2-furilo, 3-furilo, 2-tienilo, 3-tienilo, 2-piridilo, 3-piridilo, 4-piridilo, 2-pirimidilo, 4-pirimidilo, 5-benzotiazolilo, purinilo, 2-benzimidazolilo, 5-indolilo, 1-isoquinolilo, 5-isoquinolilo, 2-quinoxalinilo, 5-quinoxalinilo, 3-quinolilo, y 6-quinolilo. Los sustituyentes para cada uno de los sistemas anulares arílicos indicados antes se seleccionan del grupo de los sustituyentes aceptables descritos más abajo.The term "aryl", used only combined with other terms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwise indicated, a substituent aromatic which can be a single ring or multiple rings (up to three rings) that are fused together or joined covalently The rings can each contain from zero to four heteroatoms selected from N, O, and S, where atoms of nitrogen and sulfur are optionally oxidized, and the atoms of Nitrogen are optionally quaternized. The aryl groups that contain heteroatoms can be referred to as "heteroaryl" and can be anchored to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the aryl ring systems indicated above are selected from the group of substituents Acceptable described below.
Se pretende que el término "arilalquilo" incluya los radicales en los que un grupo arilo está unido a un grupo alquilo (p. ej., bencilo, fenetilo, piridilmetilo y similares) o un grupo heteroalquilo (p. ej., fenoximetilo, 2-piridiloximetilo, 3-(1-naftiloxi)propilo, y similares).It is intended that the term "arylalkyl" include radicals in which an aryl group is attached to a alkyl group (eg, benzyl, phenethyl, pyridylmethyl and similar) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like).
Se pretende que cada uno de los términos anteriores (p. ej., "alquilo", "heteroalquilo" y "arilo") incluya tanto las formas sustituidas como no sustituidas del radical indicado. Los sustituyentes preferidos para cada tipo de radical se proporcionan más abajo.It is intended that each of the terms above (eg, "alkyl", "heteroalkyl" and "aryl") include both substituted and non-substituted forms substituted radical indicated. Preferred substituents for Each type of radical is provided below.
Los sustituyentes para los radicales alquilo y
heteroalquilo (incluyendo los grupos referidos a menudo como
alquileno, alquenilo, heteroalquileno, heteroalquenilo, alquinilo,
cicloalquilo, heterocicloalquilo, cicloalquenilo, y
heterocicloalquenilo) pueden ser una variedad de grupos
seleccionados entre: -OR', =O, =NR', =N-OR',
-NR'R'', -SR', -halógeno, -SiR'R''R''', -OC(O)R',
-C(O)R', -CO_{2}R', -CONR'R'',
-OC(O)NR'R'', -NR''C(O)R',
-NR'-C(O)NR''R''',
-NR''C(O)_{2}R',
-NH-C(NH_{2})=NH,
-NR'C(NH_{2})=NH,
-NH-C(NH_{2})=NR', -S(O)R',
-S(O)_{2}R', -S(O)_{2}NR'R'', -CN
y
-NO_{2} en un número que oscila de cero a (2N+1), donde
N es el número total de átomos de carbono en tal radical. Cada uno
de R', R'' y R''' hace referencia independientemente a hidrógeno,
grupos alquilo C_{1}-C_{8} no sustituido y
heteroalquilo, arilo no sustituido, arilo sustituido con
1-3 halógenos, alquilo no sustituido, alcoxi o
tioalcoxi, o grupos arilalquilo C_{1}-C_{4}.
Cuando R' y R'' están unidos al mismo átomo de nitrógeno, se pueden
combinar con el átomo de nitrógeno para formar un anillo de 5, 6, o
7 miembros. Por ejemplo, se pretende que -NR'R'' incluya
1-pirrolidinilo y 4-morfolinilo. Del
estudio de sustituyentes anterior, un experto en la técnica
entenderá que se pretende que el término "alquilo" incluya
grupos tales como haloalquilo (p. ej., -CF_{3} y
-CH_{2}CF_{3}) y acilo (p. ej., -C(O)CH_{3},
-C(O)CF_{3}, -C(O)CH_{2}OCH_{3}, y
similares).Substituents for alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be a variety of groups selected from: -OR ', = O , = NR ', = N-OR', -NR'R '', -SR ', -halogen, -SiR'R''R''', -OC (O) R ', -C (O) R ', -CO_ {2} R', -CONR'R '', -OC (O) NR'R '', -NR''C (O) R ', -NR'-C (O) NR'' R ''',-NR''C (O) 2 R', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH 2) = NR ', -S (O) R', -S (O) 2 R ', -S (O) 2 NR'R'', -CN and
-NO 2 in a number that ranges from zero to (2N + 1), where N is the total number of carbon atoms in such a radical. Each of R ', R''andR''' independently refers to hydrogen, unsubstituted C 1 -C 8 alkyl and heteroalkyl groups, unsubstituted aryl, aryl substituted with 1-3 halogens, non-alkyl substituted, alkoxy or thioalkoxy, or C 1 -C 4 arylalkyl groups. When R 'and R''are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5, 6, or 7 member ring. For example, it is intended that -NR'R '' includes 1-pyrrolidinyl and 4-morpholinyl. From the study of previous substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups such as haloalkyl (eg, -CF 3 and -CH 2 CF 3) and acyl (e.g., -C (O) CH 3, -C (O) CF 3, -C (O) CH 2 OCH 3, and the like).
De un modo similar, los sustituyentes para los
grupos arilo varían y se seleccionan entre: -halógeno, -OR',
-OC(O)R', -NR'R'', -SR', -R', -CN, -NO_{2},
-CO_{2}R', -CONR'R'', -C(O)R',
-OC(O)NR'R'', -NR''C(O)R',
-NR''C(O)_{2}R',
-NR'-C(O)NR''R''',
-NH-C(NH_{2})=NH,
-NR'C(NH_{2})=NH,
-NH-C(NH_{2})=NR', -S(O)R',
-S(O)_{2}R', -S(O)_{2}NR'R'',
-N_{3}, -CH(Ph)_{2}, perfluoroalcoxi
C_{1}-C_{4}, y perfluoroalquilo
C_{1}-C_{4}, en un número que oscila de cero al
número total de valencias abiertas en el sistema anular aromático;
y donde R', R'' y R''' se seleccionan independientemente entre
hidrógeno, alquilo C_{1}-C_{8} y heteroalquilo,
arilo no sustituido, (aril no sustituido)-alquilo
C_{1}-C_{4}, y (aril no
sustituido)oxi-alquilo
C_{1}-C_{4}.Similarly, the substituents for the aryl groups vary and are selected from: -halogen, -OR ', -OC (O) R', -NR'R '', -SR ', -R', -CN, -NO_ {2}, -CO_ {2} R ', -CONR'R'', -C (O) R', -OC (O) NR'R '', -NR''C (O) R ' , -NR''C (O) 2 R ',
-NR'-C (O) NR''R ''', -NH-C (NH2) = NH, -NR'C (NH2) = NH, -NH-C (NH2 }) = NR ', -S (O) R', -S (O) 2 R ', -S (O) 2 NR'R'',
-N 3, -CH (Ph) 2, C 1 -C 4 perfluoroalkoxy, and C 1 -C 4 perfluoroalkyl, in a number ranging from zero to the total number of open valences in the aromatic ring system; and where R ', R''andR''' are independently selected from hydrogen, C 1 -C 8 alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl) -C 1 -C_ alkyl 4}, and (unsubstituted aryl) oxyC 1 -C 4 alkyl.
Dos de los sustituyentes en átomos adyacentes del anillo arílico se pueden remplazar opcionalmente por un sustituyente de la fórmula -T-C(O)-(CH_{2})_{q}-U-, donde T y U son independientemente -NH-, -O-, -CH_{2}- o un enlace sencillo, y q es un número entero de 0 a 2. Alternativamente, dos de los sustituyentes en átomos adyacentes del anillo arílico se pueden remplazar opcionalmente por un sustituyente de fórmula -A-(CH_{2})_{r}-B-, donde A y B son independientemente -CH_{2}-, -O-, -NH-, -S-, -S(O)-, -S(O)_{2}-, -S(O)_{2}NR'- o un enlace sencillo, y r es un número entero de 1 a 3. Uno de los enlaces sencillos del nuevo anillo formado de ese modo se puede remplazar opcionalmente por un enlace doble. Alternativamente, dos de los sustituyentes en átomos adyacentes del anillo arílico se pueden remplazar opcionalmente por un sustituyente de fórmula -(CH_{2})_{5}-X-(CH_{2})_{t}-, donde s y t son independientemente enteros de 0 a 3, y X es -O-, -NR'-, -S-, -S(O)-, -S(O)_{2}-, o -S(O)_{2}NR'-. El sustituyente R' en -NR'- y -S(O)_{2}NR'- se selecciona entre hidrógeno o alquilo C_{1}-C_{6} no sustituido.Two of the substituents on adjacent atoms of the aryl ring can optionally be replaced by a formula substituent -T-C (O) - (CH 2) q -U-, where T and U are independently -NH-, -O-, -CH_ {2} - or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring are they can optionally replace with a substituent of formula -A- (CH 2) r -B-, where A and B are independently -CH 2 -, -O-, -NH-, -S-, -S (O) -, -S (O) 2 -, -S (O) 2 NR'- or a single link, and r is an integer from 1 to 3. One of the simple links of the new ring formed that way can be Optionally replace with a double bond. Alternatively two of the substituents on adjacent atoms of the aryl ring are they can optionally replace with a substituent of formula - (CH 2) 5 -X- (CH 2) t -, where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2 -, or -S (O) 2 NR'-. The substituent R 'in -NR'- and -S (O) 2 NR'- is selected from hydrogen or C1-C6 alkyl unsubstituted.
Según se utiliza en la presente memoria, se pretende que el término "heteroátomo" incluya oxígeno (O), nitrógeno (N), azufre (S) y silicio (Si).As used herein, it is claims that the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
Se pretende que el término "sales farmacéuticamente aceptables" incluya sales de los compuestos activos que se preparan con ácidos o bases relativamente no tóxicos, dependiendo de los sustituyentes concretos encontrados en los compuestos descritos en la presente memoria. Cuando los compuestos de la presente invención contienen funcionalidades relativamente ácidas, se pueden obtener sale de adición de bases poniendo en contacto la forma neutra de tales compuestos con una cantidad suficiente de la base deseada, pura o en un disolvente inerte adecuado. Los ejemplos de las sales de adición de bases farmacéuticamente aceptables base incluyen la sal de sodio, potasio, calcio, amonio, amino orgánico, o magnesio, o una sal similar. Cuando los compuestos de la presente invención contienen funcionalidades relativamente alcalinas, se pueden obtener sales de adición de ácido poniendo en contacto la forma neutra de tales compuestos con una cantidad suficiente del ácido deseado, puro o en un disolvente inerte adecuado. Los ejemplos de las sales de adición de ácido farmacéuticamente aceptables incluyen aquellas derivadas de ácidos inorgánicos como los ácidos clohídrico, bromhídrico, nítrico, carbónico, monohidrogenocarbónico, fosfórico, monohidrogenofosfórico, dihidrogenofosfórico, sulfúrico, monohidrogensulfúrico, yodhídrico, o fosforoso y similares, así como las sales derivadas de ácidos orgánicos relativamente no tóxicos como acético, propiónico, isobutirico, oxálico, maleico, malónico, benzoico, succínico, subérico, fumárico, mandélico, ftálico, bencenosulfónico, p-tolilsulfónico, cítrico, tartárico, metanosulfónicoo, y similares. También están incluidas las sales de aminoácidos tales como arginato y similares, y sales de ácidos orgánicos como los ácidos glucurónico o galacturónico y similares (véase, por ejemplo, Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Algunos compuestos específicos de la presente invención contienen funcionalidades tanto alcalinas como ácidas que permiten que los compuestos se conviertan en sus sales de adición de base o ácido.The term "pharmaceutically acceptable salts" is intended to include salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, they can be obtained by adding bases by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitable inert solvent. Examples of the pharmaceutically acceptable base base addition salts include the sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When the compounds of the present invention contain relatively alkaline functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogensulfuric, iohydric, or phosphorous acids and the like, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are amino acid salts such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge, SM, et al , "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977 , 66, 1-19). Some specific compounds of the present invention contain both alkaline and acidic functionalities that allow the compounds to become their base or acid addition salts.
Las formas neutras de los compuestos se pueden regenerar poniendo en contacto la sal con una base o ácido y aislando el compuesto de origen de la manera convencional. La forma de origen del compuesto difiere de las diferentes formas salinas en algunas propiedades físicas, tales como la solubilidad en disolventes polares, pero por otra parte las sales son equivalentes a la forma de origen del compuesto para los fines de la presente invención.Neutral forms of the compounds can be regenerate by contacting the salt with a base or acid and isolating the compound of origin in the conventional manner. The shape The origin of the compound differs from the different salt forms in some physical properties, such as solubility in polar solvents, but on the other hand the salts are equivalent to the form of origin of the compound for the purposes of this invention.
Además de las formas salinas, existen las formas profármaco de los compuestos. Los profármacos de los compuestos descritos en la presente memoria son aquellos compuestos que experimentan fácilmente cambios químicos en condiciones fisiológicas para proporcionar los compuestos de la presente invención. Adicionalmente, los profármacos se pueden convertir en los compuestos de la presente invención mediante métodos químicos o bioquímicos en un entorno ex vivo. Por ejemplo, los profármacos se pueden convertir lentamente en los compuestos de la presente invención cuando se colocan en un reservorio de parche transdérmico con una enzima o un reactivo químico adecuados.In addition to the salt forms, there are prodrug forms of the compounds. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can slowly become the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Algunos compuestos de la presente invención pueden existir en formas no solvatadas así como en formas solvatadas, incluyendo las formas hidratadas. En general, las formas solvatadas son equivalentes a las formas no solvatadas y se pretende que estén incluidas en el alcance de la presente invención. Algunos compuestos de la presente invención pueden existir en formas microcristalinas múltiples o amorfas. En general, todas las formas físicas son equivalentes para los usos contemplados por la presente invención y se pretende que estén dentro del alcance de la presente invención.Some compounds of the present invention they can exist in non-solvated forms as well as in forms solvatates, including hydrated forms. In general, the solvated forms are equivalent to non-solvated forms and are intended to be included in the scope of the present invention. Some compounds of the present invention may exist in multiple or amorphous microcrystalline forms. In general, all Physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention
Algunos compuestos de la presente invención poseen átomos de carbono asimétricos (centros ópticos) o enlaces dobles; se pretende que todos los racematos, diastereómeros, isómeros geométricos e isómeros individuales estén incluidos en el alcance de la presente invención.Some compounds of the present invention they have asymmetric carbon atoms (optical centers) or bonds double; It is intended that all racemates, diastereomers, Geometric isomers and individual isomers are included in the Scope of the present invention.
Los compuestos de la presente invención pueden comprender también proporciones no naturales de isótopos atómicos en uno o más de los átomos que constituyen tales compuestos. Por ejemplo, los compuestos se pueden marcar con isótopos radiactivos, tales como por ejemplo tritio (H^{3}), yodo 125 (I^{125}) o carbono 14 (C^{14}). Se pretende que todas las variaciones isotópicas de los compuestos de la presente invención, sean radiactivos o no, estén incluidos en el alcance de la presente invención.The compounds of the present invention can also understand unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds. By example, the compounds can be labeled with radioactive isotopes, such as for example tritium (H3), iodine 125 (I125) or carbon 14 (C 14). It is intended that all variations isotopic of the compounds of the present invention, be radioactive or not, are included in the scope of this invention.
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Se ha descubierto ahora una nueva clase de compuestos que interactúan con PPAR\gamma. Dependiendo del entorno biológico (p. ej., tipo celular, condición patológica del anfitrión, etc.), estos compuestos pueden activar o bloquear las acciones de PPAR\gamma. Mediante la activación del receptor PPAR\gamma, los compuestos encontrarán uso como agentes terapéuticos capaces de modular condiciones mediadas por el receptor PPAR\gamma. Como se ha observado antes, los ejemplos de tales condiciones incluyen la NIDDM. Adicionalmente, los compuestos son útiles para la prevención y el tratamiento de las complicaciones de la diabetes (p. ej., neuropatía, retinopatía, glomerulosclerosis, y trastornos cardiovasculares), y para tratar la hiperlipidemia. Aún más, los compuestos son útiles para la modulación de condiciones inflamatorias que se ha encontrado muy recientemente están controladas por PPAR\gamma (véanse, Ricote, et al., Nature, 391:79-82 (1998) y Jiang, et al., Nature, 391:82-86 (1998)). Los ejemplos de las condiciones inflamatorias incluyen la artritis reumatoide y la aterosclerosis.A new class of compounds that interact with PPARγ has now been discovered. Depending on the biological environment ( eg , cell type, pathological condition of the host, etc. ), these compounds can activate or block the actions of PPARγ. By activating the PPARγ receptor, the compounds will find use as therapeutic agents capable of modulating conditions mediated by the PPARγ receptor. As noted above, examples of such conditions include the NIDDM. Additionally, the compounds are useful for the prevention and treatment of diabetes complications (eg, neuropathy, retinopathy, glomerulosclerosis, and cardiovascular disorders), and for treating hyperlipidemia. Even more, the compounds are useful for modulating inflammatory conditions that have been found very recently are controlled by PPARγ (see, Ricote, et al ., Nature, 391: 79-82 (1998) and Jiang, et al . , Nature, 391: 82-86 (1998)). Examples of inflammatory conditions include rheumatoid arthritis and atherosclerosis.
Los compuestos que actúan vía antagonismo de PPAR\gamma son útiles para tratar la obesidad, la hipertensión, la hiperlipidemia, la hipercolesterolemia, la hiperlipoproteinemia, y trastornos metabólicos.Compounds that act via antagonism of PPARγ are useful for treating obesity, hypertension, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, and metabolic disorders.
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En un aspecto, la presente invención proporciona compuestos que están representados por la fórmula:In one aspect, the present invention provides compounds that are represented by the formula:
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en la que el símbolo -X-Ar^{1} representa -O-piridilo. Los ejemplos de tales grupos Ar^{1} son 2-piridilo, 3-piridilo, y 4-piridilo. Más preferiblemente, Ar^{1} tiene de 1 a 2 sustituyentes seleccionados entre halógeno, -OCF_{3}, -OH, -O-alquilo C_{1}-C_{6}, -CF_{3}, alquilo C_{1}-C_{6}, o -NO_{2}. Las realizaciones más preferidas son aquellas en las que Ar^{1} está monosustituido con halógeno, -OCF_{3} o -CF_{3}.in which the symbol -X-Ar1 represents -O-pyridyl. Examples of such Ar1 groups are 2-pyridyl, 3-pyridyl, and 4-pyridyl. More preferably, Ar1 has 1 to 2 substituents selected from halogen, -OCF3, -OH, -O-C 1 -C 6 alkyl, -CF 3, C 1 -C 6 alkyl, or -NO 2. The most preferred embodiments are those in which Ar1 is monosubstituted with halogen, -OCF3 or -CF_ {3}.
La letra X representa un enlace divalente que es -O-.The letter X represents a divalent link that is -OR-.
La letra Y, en la fórmula anterior representa
una conexión divalente que es
-N(R^{12})-S(O)_{m}-, donde
R^{12} es hidrógeno, o alquilo C_{1}-C_{10};
y el subíndice m es un número entero de 0 a 2. En realizaciones
preferidas, Y representa -N(R^{12})-
S(O)_{2}-, donde R^{12} representa hidrógeno o
alquilo C_{1}-C_{6}. Muy preferiblemente, Y
representa -NH-S(O)_{2}-.
Adicionalmente, las conexiones proporcionadas en la presente memoria
(representadas por X e Y) pueden estar en cualquier
orientación.The letter Y, in the above formula represents a divalent connection that is -N (R 12) -S (O) m -, where R 12 is hydrogen, or C 1 alkyl - C 10; and the subscript m is an integer from 0 to 2. In preferred embodiments, Y represents -N (R 12) -
S (O) 2 -, where R 12 represents hydrogen or C 1 -C 6 alkyl. Most preferably, Y represents -NH-S (O) 2 -. Additionally, the connections provided herein (represented by X and Y) may be in any orientation.
El símbolo R^{1} representa un miembro seleccionado del grupo que consiste en alquilo C_{1}-C_{10}, haloalquilo C_{1}-C_{10}, -CO_{2}R^{14}, -C(O)NR^{15}R^{16}, o -C(O)R^{14}, donde R^{14} es un miembro seleccionado del grupo que consiste en hidrógeno o alquilo C_{1}-C_{10} y R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10}.The symbol R1 represents a member selected from the group consisting of alkyl C 1 -C 10, haloalkyl C 1 -C 10, -CO 2 R 14, -C (O) NR 15 R 16, or -C (O) R 14, where R 14 is a member selected from the group consisting of hydrogen or C 1 -C 10 alkyl and R 15 and R 16 are each independently hydrogen or alkyl C_ {1} -C_ {10}.
Preferiblemente, R^{1} es -alquilo C_{1}-C_{8}, o -C(O)NR^{15}R^{16}.Preferably, R1 is -alkyl C_ {1} -C_ {8}, or -C (O) NR 15 R 16.
El símbolo R^{2} representa un grupo fenilo sustituido opcionalmente con 1-3 sustituyentes seleccionados entre halógeno, -OCF_{3}, -OH, -O-alquilo C_{1}-C_{8}, -CF_{3}, -CN, -C(O)-alquilo C_{1}-C_{8}, -alquilo C_{1}-C_{8} y -NH_{2}.The symbol R2 represents a phenyl group optionally substituted with 1-3 substituents selected from halogen, -OCF3, -OH, -O-C 1 -C 8 alkyl, -CF 3, -CN, -C (O) -alkyl C 1 -C 8, -alkyl C 1 -C 8 and -NH 2.
En un grupo de realizaciones particularmente preferidas, los compuestos están representados por la fórmula I, en la que Ar^{1} es un anillo de piridilo que tiene un solo sustituyente seleccionado del grupo que consiste en halógeno, -OCF_{3}, y -CF_{3}; X es -O-; Y es una conexión divalente -NH-S(O)_{2}-; R^{1} se selecciona del grupo que consiste en alquilo C_{1}-C_{8} y -C(O)NR^{15}R^{16} donde R^{15} y R^{16} se seleccionan entre hidrógeno y alquilo C_{1}-C_{8}; y R^{2} es un anillo de fenilo, sustituido opcionalmente por 0-3 grupos seleccionados entre halógeno, alquilo C_{1}-C_{8}, -O-alquilo C_{1}-C_{8} y -CN.In a group of embodiments particularly preferred, the compounds are represented by formula I, in which Ar1 is a pyridyl ring having a single substituent selected from the group consisting of halogen, -OCF 3, and -CF 3; X is -O-; And it is a divalent connection -NH-S (O) 2 -; R1 is selected from the group consisting of C 1 -C 8 alkyl and -C (O) NR 15 R 16 where R 15 and R 16 are select between hydrogen and alkyl C 1 -C 8; and R2 is a phenyl ring, optionally substituted by 0-3 groups selected from halogen, alkyl C 1 -C 8, -O-alkyl C_ {1} -C_ {8} and -CN.
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Un experto en la técnica entenderá que algunos isómeros estructurales están representados por la fórmula I. Los isómeros preferidos son aquellos en los que los grupos en el anillo de fenilo ocupan posiciones que no son contiguas. Los compuestos particularmente preferidos son aquellos que tienen las orientaciones estructurales representadas por las fórmulas:One skilled in the art will understand that some Structural isomers are represented by formula I. The Preferred isomers are those in which the groups in the ring of phenyl occupy positions that are not contiguous. The compounds particularly preferred are those that have the orientations structural represented by the formulas:
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Los compuestos más preferidos son aquellos que tienen la orientación estructural representada por la fórmula (Ia).The most preferred compounds are those that they have the structural orientation represented by the formula (Ia).
En otro aspecto, la presente invención proporciona composiciones farmacéuticas que comprenden al menos uno de los compuestos anteriores mezclado con un excipiente farmacéuticamente aceptable.In another aspect, the present invention provides pharmaceutical compositions comprising at least one of the above compounds mixed with an excipient pharmaceutically acceptable.
En otro aspecto más, la presente invención proporciona los compuestos para su uso en la modulación de condiciones mediadas por PPAR\gamma en un anfitrión. Más concretamente, las condiciones se seleccionan entre la diabetes mellitus no insulinodependiente, la obesidad, y condiciones inflamatorias tales como, por ejemplo, la artritis reumatoide y la aterosclerosis.In yet another aspect, the present invention provides the compounds for use in the modulation of PPAR? mediated conditions on a host. Plus specifically, the conditions are selected among diabetes Non-insulin dependent mellitus, obesity, and conditions inflammatory diseases such as rheumatoid arthritis and atherosclerosis
En otro aspecto más, la presente invención proporciona métodos para modular condiciones mediadas por PPAR\gamma en un anfitrión, administrando al anfitrión una cantidad de benzobromarona que media PPAR\gamma.In yet another aspect, the present invention provides methods to modulate conditions mediated by PPAR? On a host, administering to the host a amount of benzobromarone that mediates PPARγ.
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Los compuestos de la presente invención se pueden preparar utilizando métodos sintéticos convencionales. Con fines ilustrativos, los Esquemas 1-5 ilustran métodos para la preparación de compuestos de fórmula estructural (Ia). Un experto en la técnica entenderá que se pueden emplear métodos similares para la síntesis de compuestos en las otras clases estructurales.The compounds of the present invention are They can prepare using conventional synthetic methods. With illustrative purposes, Schemes 1-5 illustrate methods for the preparation of compounds of structural formula (Ia). One skilled in the art will understand that they can be used. similar methods for the synthesis of compounds in the others structural classes
Como se muestra en el Esquema 1, los compuestos de la presente invención se pueden preparar comenzando por el éster etílico de ácido 2-cloro-5-nitrobenzoico (i) asequible comercialmente. El tratamiento de i con un fenol, tiofenol, o anilina protegida opcionalmente en presencia de una base y calor proporciona el aducto (ii). La reducción del grupo nitro en ii con H_{2} y un catalizador de Pd/C o Fe/HCl proporciona un derivado de anilina (iii). La sulfonilación de iii con un haluro de arilsulfonilo apropiado (Ar'SO_{2}Cl) en presencia de una base (típicamente una amina terciaria) proporciona un compuesto (iv) objetivo. El compuesto iv también se puede convertir en un compuesto relacionado de fórmula (v) en la que el éster carboxílico es remplazado por un anillo de 2-amino-1,3,4-oxadiazol, mediante tratamiento con semicarbazida.As shown in Scheme 1, the compounds of the present invention can be prepared starting with the ester ethyl acid 2-chloro-5-nitrobenzoic (i) commercially available. The treatment of i with a phenol, thiophenol, or optionally protected aniline in the presence of a base and heat provides the adduct (ii). The reduction of the nitro group in ii with H 2 and a Pd / C or Fe / HCl catalyst provides a aniline derivative (iii). The sulfonylation of iii with a halide of appropriate arylsulfonyl (Ar'SO2 Cl) in the presence of a base (typically a tertiary amine) provides a compound (iv) objective. Compound iv can also be converted into a related compound of formula (v) in which the carboxylic ester is replaced by a ring of 2-amino-1,3,4-oxadiazole, by treatment with semicarbazide.
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Esquema 1Scheme one
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Otros compuestos de la presente invención se pueden preparar comenzando por i (y compuestos relacionados) como se muestra en el Esquema 2. El tratamiento de i con un compuesto de aril litio o haluro de arilmagnesio (preparado a partir de los haluros de arilo correspondientes) en presencia de un catalizador de cobre (CuCN o CuCl) proporciona un aducto de biarilo (vi). Alternativamente, los aductos de biarilo tales como vi se pueden preparar directamente a partir de un haluro de arilo (Ar'-Cl o Ar'-Br) e i utilizando la reacción de Heck conocida (en presencia de paladio). La conversión de vi en dianas adecuadas sigue etapas similares a las esbozadas en el Esquema 1. Según se ha mostrado, el grupo nitro en vi se puede reducir utilizando H_{2} y un catalizador de Pd/C o Fe/HCl para proporcionar un derivado de anilina (vii). La sulfonilación de vii con un haluro de arilsulfonilo apropiado (Ar''O_{2}Cl) en presencia de una base (típicamente una amina terciaria) proporciona un compuesto (viii) objetivo. El compuesto viii también se puede convertir en un compuesto objetivo diferente (ix), como se ha descrito antes, mediante tratamiento con semicarbazida.Other compounds of the present invention are they can prepare starting with i (and related compounds) as is shown in Scheme 2. The treatment of i with a compound of aryl lithium or arylmagnesium halide (prepared from corresponding aryl halides) in the presence of a catalyst of Copper (CuCN or CuCl) provides a biaryl adduct (vi). Alternatively, biaryl adducts such as vi can be prepare directly from an aryl halide (Ar'-Cl or Ar'-Br) and i using the known Heck reaction (in the presence of palladium). The conversion of vi on appropriate targets follows similar steps to those outlined in Scheme 1. As shown, the nitro group in vi can be reduce using H2 and a catalyst of Pd / C or Fe / HCl to provide an aniline derivative (vii). The sulfonylation of vii with an appropriate arylsulfonyl halide (Ar''O2 Cl) in presence of a base (typically a tertiary amine) provides an objective compound (viii). Compound viii can also be convert into a different target compound (ix), as has been described above, by treatment with semicarbazide.
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Esquema 2Scheme 2
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La preparación de los compuestos de fórmula Ia, en los que se invierte la orientación de una conexión sulfonamida, se muestra en el Esquema 3. En pocas palabras, el ácido bencenosulfónico x (preparado mediante sulfonilación de 2-clorobenzoato de etilo asequible comercialmente) se puede tratar con un fenol, tiofenol, o anilina protegida en presencia de una base y calor para proporcionar los aductos xi, xii y xiii. La conversión de cualquiera de los aductos xi-xiii en el cloruro de sulfonilo (xiv) se logra utilizando reactivos convencionales (p. ej., cloruro de tionilo, POCl_{3}, y similares). El tratamiento del cloruro de sulfonilo (xiv) con una amina sustituida proporciona la sulfonamida (xv). Alternativamente, el cloruro de sulfonilo (xiv) se puede convertir en una sulfona (xvi) tras el tratamiento con un reactivo de Grignard adecuado (R-MgBr) o un reactivo de alquil- o aril-litio (R-Li).The preparation of the compounds of formula Ia, in which the orientation of a sulfonamide connection is reversed, is shown in Scheme 3. In a nutshell, benzenesulfonic acid x (prepared by commercially available ethyl 2-chlorobenzoate sulfonylation) is it can deal with a phenol, thiophenol, or protected aniline in the presence of a base and heat to provide adducts xi, xii and xiii. The conversion of any of the xi-xiii adducts into the sulfonyl chloride (xiv) is accomplished using conventional reagents ( eg , thionyl chloride, POCl3, and the like). Treatment of sulfonyl chloride (xiv) with a substituted amine provides sulfonamide (xv). Alternatively, the sulfonyl chloride (xiv) can be converted into a sulfone (xvi) after treatment with a suitable Grignard reagent (R-MgBr) or an alkyl- or aryl lithium (R-Li) reagent.
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Esquema 3Scheme 3
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La alteración de los grupos R^{1} se puede completar utilizando una variedad de métodos. El Esquema 4 ilustra un método para la conversión de un grupo éster en un grupo carbamato durante la construcción del compuesto objetivo. Un experto en la técnica entenderá que se pueden emplear otros procedimientos químicos para preparar compuestos relacionados de la invención. La saponificación de ii produce un ácido carboxílico que se puede convertir en la amina (xvii) vía transposición de Curtius. El tratamiento de xvii con cloroformiato de etilo en presencia de una base (típicamente una amina terciaria) produce el carbamato (xviii). La posterior reducción del grupo nitro en xviii se puede lograr utilizando los métodos esbozados antes para proporcionar xix. La conversión de xix en la sulfonamida objetivo (xx), se logra de una manera similar utilizando métodos ya indicados.The alteration of the R1 groups can be Complete using a variety of methods. Scheme 4 illustrates a method for the conversion of an ester group into a carbamate group during the construction of the target compound. An expert in technique will understand that other procedures can be used Chemicals for preparing related compounds of the invention. The Saponification of II produces a carboxylic acid that can be convert into the amine (xvii) via Curtius transposition. He xvii treatment with ethyl chloroformate in the presence of a base (typically a tertiary amine) produces carbamate (xviii). The subsequent reduction of the nitro group in xviii can be achieved using the methods outlined above to provide xix. The conversion of xix to the target sulfonamide (xx), is achieved by a similar way using methods already indicated.
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Esquema 4Scheme 4
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Otros compuestos más de la invención se pueden preparar a partir de ii, como se esboza en el Esquema 5. Así, el tratamiento de ii con metil litio (1,0 equivalentes) o hidróxido de potasio seguido de bromuro de metilmagnesio, proporciona la cetona xxi. La oxidación de Baeyer-Villegar (utilizando ácido metacloro-perbenzoico) produce el éster xxii. La reducción del grupo nitro en xxii utilizando H_{2} y un catalizador de Pd/C o Fe/HCl proporciona un derivado de anilina (xxiii). La sulfonilación de xxiii con un haluro de arilsulfonilo (Ar'SO_{2}Cl) en presencia de una base (como captador de ácido) proporciona un compuesto (xxiv) objetivo. Se pueden preparar compuestos adicionales de la invención escindiendo el grupo acetato en xxiv, y haciendo reaccionar el grupo hidroxi resultante con reactivos tales como isocianato de metilo para producir xxv.Other compounds of the invention can be prepare from ii, as outlined in Scheme 5. Thus, the treatment of ii with methyl lithium (1.0 equivalents) or hydroxide of potassium followed by methylmagnesium bromide, provides the ketone xxi. Oxidation of Baeyer-Villegar (using metachloro-perbenzoic acid) produces the ester xxii. The reduction of the nitro group in xxii using H2 and a Pd / C or Fe / HCl catalyst provides an aniline derivative (xxiii). Sulfonylation of xxiii with an arylsulfonyl halide (Ar'SO_ {Cl}) in the presence of a base (as an acid scavenger) provides a target compound (xxiv). Can be prepared additional compounds of the invention cleaving the acetate group in xxiv, and reacting the resulting hydroxy group with reagents such as methyl isocyanate to produce xxv.
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Esquema 5Scheme 5
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Los compuestos de la presente invención se pueden evaluar en cuanto a la modulación del receptor PPAR\gamma utilizando análisis tales como los descritos por Jiang, et al., Nature 391:82-86 (1998), Ricote, et al., Nature 391:79-82 (1998) y Lehmann, et al., J. Biol. Chem. 270(12): 12953-12956 (1995). Alternativamente, los compuestos se pueden evaluar en cuanto a su capacidad para desplazar BRL 49653 radiomarcado de una proteína de fusión PPAR\gamma-GST como sigue:The compounds of the present invention can be evaluated for the modulation of the PPARγ receptor using analyzes such as those described by Jiang, et al ., Nature 391: 82-86 (1998), Ricote, et al ., Nature 391 : 79-82 (1998) and Lehmann, et al ., J. Biol. Chem. 270 (12): 12953-12956 (1995). Alternatively, the compounds can be evaluated for their ability to displace radiolabeled BRL 49653 from a PPAR? -GST fusion protein as follows:
Proteína de fusión PPAR\gamma-GST (preparada de acuerdo con procedimientos convencionales), BRL 49653-[H^{3}] que tiene una actividad específica de 50 Ci/mmoles, placa de filtración Polyfiltronics Unifilter 350 y cuentas de glutationa-Sepharose® (de Pharmacia: lavadas dos veces con 10x tampón de unión en el que se puede prescindir de BSA y DTT).Fusion protein PPARγ-GST (prepared according to conventional procedures), BRL 49653- [H3] which has a specific activity of 50 Ci / mmol, filtration plate Polyfiltronics Unifilter 350 and accounts glutathione-Sepharose® (from Pharmacia: two washes times with 10x binding buffer in which BSA can be dispensed with and DTT).
Se añade tampón de unión (Tris-HCl 10 mM, pH 8,0, KCl 50 mM, DTT 10 mM, BSA al 0,02% y NP-40 al 0,01%) en cantidades de 80 microlitros a los pocillos de la placa de filtración. El compuesto de ensayo se añade después en 10 microlitros de DMSO. La proteína de fusión PPAR\gamma-GST y el compuesto BRL radiomarcado se mezclan previamente en tampón de unión que contiene DTT 10 mM y se añade en cantidades de 10 microlitros a los pocillos de la placa para proporcionar concentraciones finales de 1 \mug/pocillo de proteína de fusión PPAR\gamma-GST y compuesto BRL 49653-[H^{3}] 10 nM. La placa se incuba durante 15 minutos. Se añaden cuentas de Glutationa-agarosa en 50 \muL de tampón de unión, y la placa se sacude vigorosamente durante una hora. La placa se lava cuatro veces con 200 \muL/pocillo de tampón de unión (sin BSA ni DTT). El fondo de la placa se sella y se añaden 200 \muL/pocillo de cóctel de centelleo. Después se sella la parte superior de la placa y se determina la radiactividad.Binding Buffer is added (10 mM Tris-HCl, pH 8.0, 50 mM KCl, 10 mM DTT, BSA 0.02% and 0.01% NP-40) in quantities of 80 microliters to the wells of the filtration plate. The compound Test is then added in 10 microliters of DMSO. The protein PPAR? -GST melting and the BRL compound radiolabeled are pre-mixed in binding buffer containing 10 mM DTT and added in amounts of 10 microliters to the wells of the plate to provide final concentrations of 1 \ mug / well of fusion protein PPARγ-GST and compound BRL 49653- [H3] 10 nM. The plate is incubated for 15 minutes. Accounts of Glutathione agarose in 50 µL binding buffer, and the plate is shaken vigorously for an hour. The plate is wash four times with 200 µL / well of binding buffer (without BSA or DTT). The bottom of the plate is sealed and 200 are added µL / well of scintillation cocktail. Then the part is sealed upper plate and radioactivity is determined.
Los compuestos de la presente invención se pueden preparar y administrar en una amplia gama de formas de dosificación orales y parenterales. Así, los compuestos de la presente invención se pueden administrar mediante inyección, esto es, intravenosamente, intramuscularmente, intracutáneamente, subcutáneamente, intraduodenalmente, o intraperitonealmente. Asimismo, los compuestos descritos en la presente memoria se pueden administrar mediante inhalación, por ejemplo, intranasalmente. Adicionalmente, los compuestos de la presente invención se pueden administrar transdérmicamente. Por lo tanto, la presente invención también proporciona composiciones farmacéuticas que comprenden un portador o excipiente farmacéuticamente aceptables y un compuesto de fórmula (I) o una sal farmacéuticamente aceptable de un compuesto de fórmula (I).The compounds of the present invention are can prepare and administer in a wide range of ways oral and parenteral dosing. Thus, the compounds of the The present invention can be administered by injection, this it is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administer by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administer transdermally. Therefore, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).
Para preparar composiciones farmacéuticas a partir de los compuestos de la presente invención, los portadores farmacéuticamente aceptables pueden ser sólidos o líquidos. Las preparaciones en forma sólida incluyen polvos, comprimidos, píldoras, cápsulas, sellos, supositorios, y gránulos dispersables. Un portador sólido puede ser una o más sustancias que pueden actuar también como diluyentes, agentes aromatizantes, aglutinantes, conservantes, comprimidos, agentes disgregantes, o material encapsulante.To prepare pharmaceutical compositions a from the compounds of the present invention, the carriers Pharmaceutically acceptable can be solid or liquid. The Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier can be one or more substances that can act also as diluents, flavoring agents, binders, preservatives, tablets, disintegrating agents, or material encapsulant
En los polvos, el portador es un sólido finamente dividido que está mezclado con el componente activo finamente dividido. En los comprimidos, el componente activo se mezcla con el portador que tiene las propiedades aglutinantes deseadas en la proporciones adecuadas y se compacta en la forma y el tamaño deseados.In powders, the carrier is a solid finely divided which is mixed with the active component finely divided. In tablets, the active component is mixture with the carrier that has the binder properties desired in the appropriate proportions and compacted in the form and the desired size.
Los polvos y comprimidos contienen preferiblemente del 5% o 10% al 70% del compuesto activo. Los portadores adecuados son carbonato de magnesio, estearato de magnesio, talco, azúcar, lactosa, pectina, dextrina, almidón, gelatina, tragacanto, metilcelulosa, carboximetilcelulosa sódica, una cera de bajo punto de fusión, manteca de cacao, y similares. Se pretende que el término "preparación" incluya la formulación del compuesto activo con el material encapsulante como portador proporcionando una cápsula en la que el componente activo con o sin otros portadores, está rodeado por un portador, que de este modo se asocia con él. De un modo similar, están incluidos los sellos y las grageas. Los comprimidos, los polvos, las cápsulas, las píldoras, los sellos, y las grageas se pueden utilizar como formas de dosificación sólidas adecuadas para la administración oral.Powders and tablets contain preferably 5% or 10% to 70% of the active compound. The Suitable carriers are magnesium carbonate, stearate magnesium, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Be It is intended that the term "preparation" includes the formulation of the active compound with the encapsulating material as carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which thus Associate with him. Similarly, seals and stamps are included. dragees Tablets, powders, capsules, pills, seals, and dragees can be used as forms of solid dosage suitable for oral administration.
Para preparar supositorios, se funde primero una cera de bajo punto de fusión, tal como una mezcla de glicéridos de ácidos grasos o manteca de cacao y el componente activo se dispersa homogéneamente allí, por ejemplo agitando. La mezcla homogénea fundida se vierte después en moldes del tamaño conveniente, se deja enfriar, y de ese modo se solidifica.To prepare suppositories, a low melting wax, such as a mixture of glycerides of fatty acids or cocoa butter and the active component is dispersed homogeneously there, for example by stirring. The homogeneous mixture molten is then poured into molds of suitable size, left cool, and thereby solidify.
Las preparaciones en forma líquida incluyen soluciones, suspensiones, y emulsiones, por ejemplo, soluciones de agua o de agua/propilenglicol. Para la inyección parenteral, se pueden formular preparaciones líquidas en solución en soluciones acuosas de polietilenglicol.Liquid form preparations include solutions, suspensions, and emulsions, for example, solutions of water or water / propylene glycol. For parenteral injection, it they can formulate liquid preparations in solution in solutions aqueous polyethylene glycol.
Las soluciones acuosas adecuadas para uso oral se pueden preparar disolviendo el componente activo en agua y añadiendo colorantes, aromas, estabilizadores, y agentes espesantes adecuados según se desee. Las suspensiones acuosas adecuadas para uso oral se pueden elaborar dispersando el componente activo finamente dividido en agua con sustancias viscosas, tales como gomas naturales o sintéticas, resinas, metilcelulosa, carboximetilcelulosa sódica, y otros agentes suspensores bien conocidos.Aqueous solutions suitable for oral use they can be prepared by dissolving the active component in water and adding dyes, aromas, stabilizers, and thickening agents suitable as desired. Aqueous suspensions suitable for oral use can be made by dispersing the active component finely divided into water with viscous substances, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents well known.
También están incluidas las preparaciones en forma sólida que se pretende que se conviertan, inmediatamente después de su uso, en preparaciones en forma líquida para la administración oral. Tales formas líquidas incluyen soluciones, suspensiones, y emulsiones. Estas preparaciones pueden contener, además del componente activo, colorantes, aromas, estabilizadores, tampones, edulcorantes artificiales y naturales, dispersantes, espesantes, agentes solubilizantes, y similares.Preparations are also included in solid form that is intended to be converted, immediately after use, in liquid form preparations for oral administration Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, dyes, aromas, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
La preparación farmacéutica está preferiblemente en una forma de dosificación unitaria. En tal forma la preparación está subdividida en dosis unitarias que contienen cantidades apropiadas del componente activo. La forma de dosificación unitaria puede ser una preparación envasada, conteniendo el envase cantidades discretas de preparación, tal como comprimidos, cápsulas, y polvos envasados en viales o ampollas. Asimismo, la forma de dosificación unitaria puede ser la cápsula, el comprimido, el sello, o la gragea en sí mismos, o puede tener el número apropiado de cualquiera de estas en forma envasada.The pharmaceutical preparation is preferably in a unit dosage form. In such form the preparation is subdivided into unit doses that contain quantities appropriate active component. The unit dosage form it can be a packaged preparation, the package containing quantities discrete preparation, such as tablets, capsules, and powders packaged in vials or ampoules. Also, the dosage form Unitary can be the capsule, the tablet, the seal, or the dragee in themselves, or you can have the appropriate number of any of You are in packaged form.
La cantidad de componente activo en una preparación de dosificación unitaria se puede variar o ajustar de 0,1 mg a 1.000 mg, preferiblemente de 1,0 mg a 100 mg de acuerdo con la aplicación concreta y la potencia del componente activo. La composición puede, si se desea, contener también otros agentes terapéuticos compatibles.The amount of active component in a Unit dosage preparation can be varied or adjusted from 0.1 mg to 1,000 mg, preferably 1.0 mg to 100 mg according to the specific application and the power of the active component. The composition may, if desired, also contain other agents Therapeutic compatible.
En el uso terapéutico para el tratamiento de la obesidad, la NIDDM, o las condiciones inflamatorias, los compuestos se administran a la dosificación inicial de aproximadamente 0,001 mg/kg a aproximadamente 100 mg/kg al día. Se prefiere un intervalo de dosificación diario que oscila de aproximadamente 0,1 mg/kg a aproximadamente 10 mg/kg. Las dosificaciones, no obstante, pueden variar dependiendo de los requerimientos del paciente, la gravedad de la condición que esté siendo tratada, y el compuesto que esté siendo empleado. La determinación de la dosificación apropiada para una situación concreta se encuentra en el conocimiento práctico del experto. Generalmente, el tratamiento se inicia con dosificaciones menores que la dosis óptima del compuesto. Después de eso, la dosificación se aumenta por medio de pequeños incrementos hasta que se alcanza el efecto óptimo en esas circunstancias. Por conveniencia, la dosificación diaria total se puede dividir y administrar en porciones durante el día, si se desea.In therapeutic use for the treatment of Obesity, NIDDM, or inflammatory conditions, compounds administered at the initial dosage of approximately 0.001 mg / kg at approximately 100 mg / kg daily. An interval is preferred daily dosage ranging from approximately 0.1 mg / kg to approximately 10 mg / kg Dosages, however, may vary depending on patient requirements, severity of the condition being treated, and the compound that is being being employed Determination of the appropriate dosage for a specific situation is found in the practical knowledge of expert. Generally, treatment begins with dosages less than the optimal dose of the compound. After that, the dosage is increased by small increments until the optimum effect is achieved in these circumstances. By convenience, the total daily dosage can be divided and administer in portions during the day, if desired.
Los siguientes ejemplos se ofrecen a modo de ilustración y no se pretende que limiten el alcance de la invención.The following examples are offered by way of illustration and are not intended to limit the scope of the invention.
Los reactivos y disolventes utilizados más abajo se pueden obtener a partir de Fuentes comerciales tales como Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Los espectros de RMN H^{1} se registraron en un espectrómetro de RMN Varian Gemini 400 MHz. Los picos significativos se tabularon en el orden: número de protones, multiplicidad (s, singlete; d, doblete; t, triplete; q, cuartete; m, multiplete; br s, singlete ancho) y constante de acoplamiento en Hertzios. Los espectros de masas de Ionización Electrónica (IE) se registraron en un espectrómetro Hewlett Packard 5989A. Los resultados de la espectrometría de masas son referidos como la proporción de masa a carga, seguido de la abundancia relativa de cada ión (entre paréntesis). En las tablas, se informa sobre un solo valor m/e para el ión M+H (o según se indique M-H) que contiene los isótopos atómicos más comunes. Los patrones isotópicos corresponden a la formula esperada en todos los casos. El análisis de espectrometría de masas de Ionización por Electropulverización (ESI) se realizó en un espectrómetro de masas de electropulverización Hewlett-Packard 1100 MSD utilizando HPLC HP1100 para la liberación de la muestra. Normalmente el analito se disolvió en metanol a 0,1 mg/mL y se infundió 1 microlitro con el disolvente de liberación en el espectrómetro de masas barriendo de 100 a 1500 daltons. Todos los compuestos pudieron ser analizados en el modo ESI positivo, utilizando acetonitrilo/agua 1:1 con ácido acético al 1% como disolvente de liberación. Los compuestos proporcionados más abajo se podrían analizar también en el modo ESI negativo, utilizando NH_{4}OAc 2 mM en acetonitrilo/agua como disolvente de liberación.Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). The spectra of 1 H NMR were recorded on a Varian Gemini NMR spectrometer 400 MHz. Significant peaks were tabulated in the order: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartete; m, multiplet; br s, wide singlet) and constant of Hertz coupling. Ionization mass spectra Electronics (IE) were recorded on a Hewlett Packard spectrometer 5989A. The results of mass spectrometry are referred as the proportion of mass to load, followed by abundance relative of each ion (in parentheses). In the tables, it is reported over a single m / e value for the M + H ion (or as indicated M-H) that contains the most common atomic isotopes. Isotopic patterns correspond to the expected formula in all the cases. Ionization mass spectrometry analysis by Electropulverization (ESI) was performed on a mass spectrometer electrospray Hewlett-Packard 1100 MSD using HPLC HP1100 for sample release. Usually the analyte was dissolved in methanol at 0.1 mg / mL and infused 1 microliter with the release solvent in the spectrometer of masses sweeping 100 to 1500 daltons. All the compounds could be analyzed in the positive ESI mode, using 1: 1 acetonitrile / water with 1% acetic acid as solvent release. The compounds provided below could be analyze also in the negative ESI mode, using NH4 OAc 2 mM in acetonitrile / water as release solvent.
Este ejemplo ilustra la preparación de 5-amino-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5-amino-2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
A una solución agitada del óxido de piridina (262 mg, 0,849 mmoles, asequible de Maybridge Chemical Company, Cornwall, UK) en MeOH (5 mL) se le añadió níquel Raney (1 g, 8,5 mmoles, suspensión al 50% en agua) gota a gota. Al cabo de 2 horas, la mezcla se filtró a través de Celite® y la solución se evaporó para dar 169 mg del compuesto del título en forma de un aceite, que se utilizó sin purificación adicional.To a stirred solution of pyridine oxide (262 mg, 0.849 mmol, available from Maybridge Chemical Company, Cornwall, UK) in MeOH (5 mL) Raney nickel (1 g, 8.5) was added mmol, 50% suspension in water) drop by drop. After 2 hours, the mixture was filtered through Celite® and the solution was evaporated to give 169 mg of the title compound as an oil, which It was used without further purification.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,13 (3H, t); 4,16 (2H, q); 6,98 (2H, s); 7,21 (1H, s); 7,29 (1H, s); 8,09 (1H, s); 8,19 (1H, s).1 H NMR (400 MHz) (CD 3 OD) δ 1.13 (3H, t); 4.16 (2H, q); 6.98 (2H, s); 7.21 (1H, s); 7.29 (1H, s); 8.09 (1H, s); 8.19 (1H, s).
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Este ejemplo ilustra la preparación de 5-amino-2-(3-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5-amino-2- (3-pyridyloxy) benzoate of ethyl.
A una solución agitada del producto del Ejemplo 1 (101 mg, 0,344 mmoles) en MeOH (4 mL) se le añadió una cantidad catalítica de paladio sobre carbono. El matraz se vació de aire y se colocó bajo un balón de gas hidrógeno. Al cabo de 1 hr, la mezcla se filtró a través de Celite® y el producto filtrado se evaporó para proporcionar 85 mg del compuesto del título (96%).To a stirred solution of the product of Example 1 (101 mg, 0.344 mmol) in MeOH (4 mL) was added an amount Palladium on carbon catalytic. The flask was drained of air and placed under a balloon of hydrogen gas. After 1 hr, the mixture was filtered through Celite® and the filtrate was evaporated to provide 85 mg of the title compound (96%).
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,16 (3H, m); 4,19 (2H, m); 7,17 (2H, m); 7,52 (1H, d); 7,79 (2H, br s); 8,41 (2H, br d).1 H NMR (400 MHz) (CD 3 OD) δ 1.16 (3H, m); 4.19 (2H, m); 7.17 (2H, m); 7.52 (1H, d); 7.79 (2H, br s); 8.41 (2H, br d).
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Este ejemplo ilustra la síntesis de 5-(2-metoxi-5-bromobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the synthesis of 5- (2-Methoxy-5-bromobenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
A una solución de la anilina producida en el Ejemplo 1 (250 mg, 0,85 mmoles) en CH_{2}Cl_{2} (4 mL) se le añadió cloruro de 5-bromo-2-metoxibencenosulfonilo (244 mg, 0,85 mmoles). La mezcla se agitó durante 10 hr. El compuesto del título (94 mg, 20%) se aisló después de la cromatografía en columna de gel de sílice (1:1 hexano/acetato de etilo).To a solution of the aniline produced in the Example 1 (250 mg, 0.85 mmol) in CH 2 Cl 2 (4 mL) was given added chloride 5-Bromo-2-methoxybenzenesulfonyl (244 mg, 0.85 mmol). The mixture was stirred for 10 hr. He title compound (94 mg, 20%) was isolated after silica gel column chromatography (1: 1 hexane / acetate ethyl).
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,20 (1H, d, J = 2 Hz), 8,03 (1H, d, J = 2 Hz), 7,89 (1H, d, J = 3 Hz), 7,70 (1H, d, J = 3 Hz), 7,65 (1H, dd, J = 9, 3 Hz), 7,41 (1H, dd, J = 9, 3 Hz), 7,15 (1H, d, J = 2 Hz), 7,08 (2H, dd, J = 9, 3 Hz), 4,16 (2H, q, J = 7 Hz), 3,95 (3H, s), 1,26 (3H, t, J = 7 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.20 (1H, d, J = 2 Hz), 8.03 (1H, d, J = 2 Hz), 7.89 (1H, d, J = 3 Hz), 7.70 (1H, d, J = 3 Hz), 7.65 (1H, dd, J = 9, 3 Hz), 7.41 (1H, dd, J = 9, 3 Hz), 7.15 (1H, d, J = 2 Hz), 7.08 (2H, dd, J = 9, 3 Hz), 4.16 (2H, q, J = 7 Hz) , 3.95 (3H, s), 1.26 (3H, t, J = 7 Hz).
Alternativamente, la poli(4-vinilpiridina) (250 mg, malla 60) se puede lavar con diclorometano (2 x 7 mL) y diluir en diclorometano (2 mL). Se puede añadir la anilina producida en el Ejemplo 1 (29,2 mg, 0,1 mmoles) seguido de cloruro de 5-bromo-2-metoxibencenosulfonilo (59 mg, 0,25 mmoles). El recipiente de reacción se agita después durante diez horas y se añade ArgoPore-NH_{2} (0,50 g, carga de 1,11 mmoles/gramo) junto con diclorometano (6 mL). La vasija de reacción se agita durante 3 horas y se recoge el disolvente. La resina se lava con diclorometano (2 x 6 mL) y el diclorometano se combina y se evapora para producir el compuesto del título.Alternatively, the poly (4-vinylpyridine) (250 mg, 60 mesh) se can be washed with dichloromethane (2 x 7 mL) and dilute in dichloromethane (2 mL). The aniline produced in Example 1 can be added (29.2 mg, 0.1 mmol) followed by 5-Bromo-2-methoxybenzenesulfonyl (59 mg, 0.25 mmol). The reaction vessel is then stirred. for ten hours and ArgoPore-NH2 is added (0.50 g, 1.11 mmol / gram load) together with dichloromethane (6 mL) The reaction vessel is stirred for 3 hours and the solvent The resin is washed with dichloromethane (2 x 6 mL) and the dichloromethane is combined and evaporated to produce the compound of Title.
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Este ejemplo ilustra la síntesis de 5-(3,4-dimetoxibencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the synthesis of 5- (3,4-dimethoxybenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
El compuesto del título se preparó de una manera similar al Ejemplo 3, comenzando con 0,1 g de la anilina del Ejemplo 1 y cloruro de 3,4-dimetoxibencenosulfonilo, y añadiendo 0,2 mL de piridina a la mezcla de reacción para producir 0,115 g (68%) de la sulfonamida del título.The title compound was prepared in a manner. similar to Example 3, starting with 0.1 g of the aniline from Example 1 and 3,4-dimethoxybenzenesulfonyl chloride, and adding 0.2 mL of pyridine to the reaction mixture to produce 0.115 g (68%) of the title sulfonamide.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,22 (d, 1H, J = 2 Hz), 8,05 (d, 1H, J = 2 Hz), 7,68 (d, 1H, J = 3 Hz), 7,38 (m, 2H), 7,27 (d, 1H, J = 2 Hz), 7,20 (d, 1H, J = 2 Hz), 7,10 (d, 1H, J = 8 Hz), 7,01 (d, 1H, J = 8 Hz), 4,16 (q, 2H, J = 7 Hz), 3,85 (s, 3H), 3,81 (s, 3H), 1,11 (t, J = 7 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.22 (d, 1H, J = 2 Hz), 8.05 (d, 1H, J = 2 Hz), 7.68 (d, 1H, J = 3 Hz), 7.38 (m, 2H), 7.27 (d, 1H, J = 2 Hz), 7.20 (d, 1H, J = 2 Hz), 7, 10 (d, 1H, J = 8 Hz), 7.01 (d, 1H, J = 8 Hz), 4.16 (q, 2H, J = 7 Hz), 3.85 (s, 3H), 3 , 81 (s, 3H), 1.11 (t, J = 7 Hz).
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Este ejemplo ilustra la síntesis de 5-(2-metil-5-nitrobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the synthesis of 5- (2-methyl-5-nitrobenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
El compuesto del título se preparó utilizando el procedimiento descrito en el Ejemplo 3, comenzando con 0,1 g de la anilina del Ejemplo 1 y cloruro de 2-metil-5-nitrobencenosulfonilo y añadiendo poli(4-vinilpiridina) (250 mg, malla 60) a la mezcla de reacción. Después de la elaboración, se obtuvieron 0,15 g (89%) de la sulfonamida del título.The title compound was prepared using the procedure described in Example 3, starting with 0.1 g of the aniline of Example 1 and chloride 2-methyl-5-nitrobenzenesulfonyl and adding poly (4-vinylpyridine) (250 mg, 60 mesh) to the reaction mixture. After processing, it they obtained 0.15 g (89%) of the title sulfonamide.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,72 (d, 1H, J = 2 Hz), 8,32 (d, 1H, J = 8 Hz), 8,20 (d, 1H, J = 2 Hz), 8,04 (d, 1H, J = 2 Hz), 7,68 (d, 1H, J = 2 Hz), 7,63 (d, 1H, J = 8 Hz), 7,38 (d, 1H, J = 8 Hz), 7,17 (d, 1H, J = 2 Hz), 7,12 (d, 1H, J = 8 Hz), 4,15 (q, 2H, J = 7 Hz), 2,76 (s, 3H), 1,11 (t, J = 7 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.72 (d, 1H, J = 2 Hz), 8.32 (d, 1H, J = 8 Hz), 8.20 (d, 1H, J = 2 Hz), 8.04 (d, 1H, J = 2 Hz), 7.68 (d, 1H, J = 2 Hz), 7.63 (d, 1H, J = 8 Hz), 7.38 (d, 1H, J = 8 Hz), 7.17 (d, 1H, J = 2 Hz), 7.12 (d, 1H, J = 8 Hz), 4.15 (q , 2H, J = 7 Hz), 2.76 (s, 3H), 1.11 (t, J = 7 Hz).
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Este ejemplo ilustra la preparación de 5-(2,6-diclorobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (2,6-Dichlorobenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
El compuesto del título se preparó utilizando el procedimiento descrito en el Ejemplo 3, comenzando con 0,1 g de la anilina del Ejemplo 1 y cloruro de 2,6-diclorobencenosulfonilo y utilizando dimetilformamida como disolvente en lugar de CH_{2}Cl_{2}. Después de la elaboración, se obtuvieron 0,024 g (14%) de la sulfonamida del título.The title compound was prepared using the procedure described in Example 3, starting with 0.1 g of the aniline of Example 1 and chloride 2,6-dichlorobenzenesulfonyl and using dimethylformamide as solvent instead of CH 2 Cl 2. After processing, 0.024 g (14%) of the title sulfonamide.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,21 (d, 1H, J = 2 Hz), 8,02 (d, 1H, J = 8 Hz), 7,76 (d, 1H, J = 2 Hz), 7,40 - 7,58 (m, 4H), 7,17 (d, 1H, J = 2 Hz), 7,10 (d, 1H, J = 8 Hz), 4,16 (q, 2H, J = 7 Hz), 1,13 (t, J = 7 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.21 (d, 1H, J = 2 Hz), 8.02 (d, 1H, J = 8 Hz), 7.76 (d, 1H, J = 2 Hz), 7.40-7.58 (m, 4H), 7.17 (d, 1H, J = 2 Hz), 7.10 (d, 1H, J = 8 Hz ), 4.16 (q, 2H, J = 7 Hz), 1.13 (t, J = 7 Hz).
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Este ejemplo ilustra la preparación de 5-(2,4-dicloro-6-metilbencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (2,4-Dichloro-6-methylbenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
El compuesto del título se preparó utilizando procedimiento alternativo descrito en el Ejemplo 3. De esta manera, se combinaron 0,1 g de la anilina del Ejemplo 1 con cloruro de 2,4-dicloro-6-metilbencenosulfonilo y polivinilpiridina para proporcionar 0,162 g (92%) de la sulfonamida del título después de la cromatografía.The title compound was prepared using alternative procedure described in Example 3. In this way, 0.1 g of the aniline of Example 1 were combined with 2,4-dichloro-6-methylbenzenesulfonyl and polyvinylpyridine to provide 0.162 g (92%) of the title sulfonamide after chromatography.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,21 (d, 1H, J = 2 Hz), 8,04 (d, 1H, J = 2 Hz), 7,72 (d, 1H, J = 2 Hz), 7,50 (s, 1H), 7,31 - 7,38 (m, 2H), 7,17 (s, 1H), 7,10 (d, 1H, J = 9 Hz), 4,17 (q, 2H, J = 7 Hz), 2,67 (s, 3H), 1,12 (t, J = 7 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.21 (d, 1H, J = 2 Hz), 8.04 (d, 1H, J = 2 Hz), 7.72 (d, 1H, J = 2 Hz), 7.50 (s, 1H), 7.31-7.38 (m, 2H), 7.17 (s, 1H), 7.10 (d, 1H, J = 9 Hz), 4.17 (q, 2H, J = 7 Hz), 2.67 (s, 3H), 1.12 (t, J = 7 Hz).
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Este ejemplo ilustra la preparación de 5-(4-clorobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etiloThis example illustrates the preparation of 5- (4-Chlorobenzenesulfonamido) -2- (3-Chloro-5-pyridyloxy) benzoate of ethyl
A una solución agitada de la anilina producida en el Ejemplo 1 (168 mg, 0,574 mmoles) en CH_{2}Cl_{2} (3 mL) se le añadió cloruro de 4-clorobencenosulfonilo (157 mg, 0,746 mmoles, comercialmente asequible de Aldrich) de una vez. Al cabo de 20 minutos, se añadió una cantidad adicional (48 mg, 0,230 mmoles) de cloruro de 4-clorobencenosulfonilo y la solución se agitó durante la noche. El producto se aisló después de la cromatografía en columna (hexano/éter dietílico 1:1). Rendimiento: 160 mg (60%).To a stirred solution of the aniline produced in Example 1 (168 mg, 0.574 mmol) in CH 2 Cl 2 (3 mL) 4-Chlorobenzenesulfonyl chloride (157 was added mg, 0.746 mmol, commercially available from Aldrich) at once. After 20 minutes, an additional amount (48 mg, 0.230 mmol) of 4-chlorobenzenesulfonyl chloride and the solution was stirred overnight. The product was isolated after column chromatography (hexane / diethyl ether 1: 1). Yield: 160 mg (60%).
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,14 (3H, t); 4,19 (2H, q); 6,98 (2H, s); 7,13 (1H, d); 7,24 (1H, d); 7,42 (1H, m); 7,57 (2H, d); 7,69 (1H, d); 7,79 (2H, d); 8,09 (1H, s); 8,25 (1H, s).1 H NMR (400 MHz) (CD 3 OD) δ 1.14 (3H, t); 4.19 (2H, q); 6.98 (2H, s); 7.13 (1H, d); 7.24 (1H, d); 7.42 (1 H, m); 7.57 (2H, d); 7.69 (1H, d); 7.79 (2H, d); 8.09 (1H, s); 8.25 (1H, s).
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Este ejemplo ilustra la preparación de 5-(4-clorobencenosulfonamido)-2-(3-piridiloxi)benzoato de etiloThis example illustrates the preparation of 5- (4-Chlorobenzenesulfonamido) -2- (3-pyridyloxy) benzoate of ethyl
A una solución agitada de la anilina producida en el Ejemplo 2 (82 mg, 0,32 mmoles) en MeOH (3 mL) y THF (1 mL) se le añadió cloruro de 4-clorobencenosulfonilo (74 mg, 0,35 mmoles) seguido de Et_{3}N (89 \muL, 0,64 mmoles). Al cabo de 20 minutos se añadió una cantidad adicional de MeOH (1 mL) para ayudar a la disolución de los reactivos y la mezcla de reacción se dejó agitando durante la noche. En este momento, el disolvente se eliminó y el residuo se disolvió en CH_{2}Cl_{2}. La solución resultante se lavó tres veces con agua y una vez con salmuera. La capa orgánica se evaporó y el residuo resultante se purificó mediante cromatografía (1:1 hexano/éter dietílico) para proporcionar 43,6 mg del compuesto del título (rendimiento 32%).To a stirred solution of the aniline produced in Example 2 (82 mg, 0.32 mmol) in MeOH (3 mL) and THF (1 mL), he added 4-chlorobenzenesulfonyl chloride (74 mg, 0.35 mmol) followed by Et 3 N (89 µL, 0.64 mmol). After of 20 minutes an additional amount of MeOH (1 mL) was added to help dissolve the reagents and the reaction mixture will He left stirring overnight. At this time, the solvent is removed and the residue was dissolved in CH2Cl2. The solution resulting was washed three times with water and once with brine. The organic layer was evaporated and the resulting residue was purified by chromatography (1: 1 hexane / diethyl ether) to provide 43.6 mg of the title compound (32% yield).
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,14 (3H, t); 4,19 (2H, q); 7,19 (1H, d); 7,24 (1H, m); 7,38 (2H, m); 7,57 (2H, d); 7,65 (1H, d); 7,79 (2H, d); 8,15 (1H, s); 8,25 (1H, s).1 H NMR (400 MHz) (CD 3 OD) δ 1.14 (3H, t); 4.19 (2H, q); 7.19 (1H, d); 7.24 (1 H, m); 7.38 (2H, m); 7.57 (2H, d); 7.65 (1H, d); 7.79 (2H, d); 8.15 (1H, s); 8.25 (1H, s).
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Este ejemplo ilustra la preparación de ácido 5-(4-clorobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoico.This example illustrates the acid preparation 5- (4-Chlorobenzenesulfonamido) -2- (3-Chloro-5-pyridyloxy) benzoic.
A una solución agitada del producto del Ejemplo 8 (81 mg, 0,170 mmoles) en MeOH (3 mL) y agua (1,0 mL) se le añadió LiOH (89,6 mg, 3,74 mmoles). La solución se agitó durante la noche y el disolvente se evaporó para producir un sólido de color blanco que se recristalizó en cloroformo/etanol. Rendimiento aislado del compuesto del título: 46,5 mg, 61%.To a stirred solution of the product of Example 8 (81 mg, 0.175 mmol) in MeOH (3 mL) and water (1.0 mL) was added LiOH (89.6 mg, 3.74 mmol). The solution was stirred overnight and the solvent was evaporated to produce a white solid which was recrystallized from chloroform / ethanol. Isolated performance of title compound: 46.5 mg, 61%.
RMN H^{1} (400 MHz) (DMSO-D_{6}) \delta 7,18 (1H, d); 7,33 (1H, d); 7,35 (1H, m); 7,62 (1H, d); 7,66 (2H, d); 7,77 (2H, d); 8,16 (1H, d); 8,33 (1H, s); 10,60 (1H, s).1 H NMR (400 MHz) (DMSO-D 6) δ 7.18 (1H, d); 7.33 (1H, d); 7.35 (1 H, m); 7.62 (1H, d); 7.66 (2H, d); 7.77 (2H, d); 8.16 (1H, d); 8.33 (1H, s); 10.60 (1H, s).
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Este ejemplo ilustra la preparación de 5-(4-clorobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of 5- (4-Chlorobenzenesulfonamido) -2- (3-Chloro-5-pyridyloxy) benzamide.
A una solución agitada del ácido del Ejemplo 10 (20 mg, 0,046 mmoles) en CH_{2}Cl_{2} (0,5 mL) y piridina (0,5 mL) se le añadió cloruro de tionilo (17 mL, 0,228 mmoles). Al cabo de una hora, la solución se evaporó y se colocó a vacío durante la noche. El residuo se disolvió después en MeOH (1 mL) y CH_{2}Cl_{2} (1 mL) y se añadió gota a gota NH_{3} (0,12 mL, 0,227 mmoles, solución 0,757 M en etanol). La mezcla se agitó durante 8 horas y el disolvente se evaporó. El residuo se purificó mediante cromatografía (hexano/éter dietílico 1:1) para producir 7,3 mg del compuesto del título (37%).To a stirred solution of the acid of Example 10 (20 mg, 0.046 mmol) in CH 2 Cl 2 (0.5 mL) and pyridine (0.5 mL) thionyl chloride (17 mL, 0.228 mmol) was added. After one hour, the solution was evaporated and placed under vacuum during night. The residue was then dissolved in MeOH (1 mL) and CH 2 Cl 2 (1 mL) and NH 3 (0.12 mL, was added dropwise) 0.277 mmol, 0.757 M solution in ethanol). The mixture was stirred. for 8 hours and the solvent was evaporated. The residue was purified by chromatography (hexane / diethyl ether 1: 1) to produce 7.3 mg of the title compound (37%).
RMN H^{1} (400 MHz) (CDCl_{3}) 6,67 (1H, d); 7,10 (1H, d); 7,23 (5H, m, interc. 1H); 7,52 (2H, d); 7,89 (2H, d); 8,21 (1H, s exch); 8,45 (1H, interc.).1 H NMR (400 MHz) (CDCl 3) 6.67 (1H, d); 7.10 (1H, d); 7.23 (5H, m, interc. 1H); 7.52 (2H, d); 7.89 (2H, d); 8.21 (1H, s exch); 8.45 (1H, interc.).
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Este ejemplo ilustra la preparación de 5-(2,4-dicloro-5-metilbencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (2,4-Dichloro-5-methylbenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
El compuesto del título se puede preparar de una manera similar al Ejemplo 3, comenzando con cloruro de 2,4-dicloro-5-metilbencenosulfonilo, o se puede adquirir de Maybridge Chemical Co.The title compound can be prepared in one similar to Example 3, starting with 2,4-dichloro-5-methylbenzenesulfonyl, or can be purchased from Maybridge Chemical Co.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,13 (3H, t); 2,39 (3H, s); 4,18 (2H, q); 7,10 (1H, d); 7,19 (1H, d); 7,42 (1H, dd); 7,64 (1H, s); 7,72 (1H, d); 8,01 (1H, s); 8,06 (1H, d); 8,22 (1H, d).1 H NMR (400 MHz) (CD 3 OD) δ 1.13 (3H, t); 2.39 (3H, s); 4.18 (2H, q); 7.10 (1H, d); 7.19 (1H, d); 7.42 (1H, dd); 7.64 (1H, s); 7.72 (1H, d); 8.01 (1H, s); 8.06 (1H, d); 8.22 (1H, d).
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Este ejemplo ilustra la síntesis de 2-(5-cloro-3-piridiloxi)-5-(2,4-dicloro-5-metilbencenosulfonamido)-benzamidas. En pocas palabras, el ácido benzoico precursor (0,050 g) se disolvió en diclorometano (2 mL) y se añadió PyBroP (5 eq., 230 mg) seguido de la amina (5 equiv.) y diisopropiletilamina (2 equiv.). La solución resultante se agitó a temperatura ambiente durante ocho hr y se filtró a través de un lecho de gel de sílice. El producto se obtuvo en forma de un sólido de color blanco después de la HPLC a escala preparativa.This example illustrates the synthesis of 2- (5-Chloro-3-pyridyloxy) -5- (2,4-dichloro-5-methylbenzenesulfonamido) -benzamides. Simply put, the precursor benzoic acid (0.050 g) is dissolved in dichloromethane (2 mL) and PyBroP (5 eq., 230 mg) was added followed by the amine (5 equiv.) and diisopropylethylamine (2 equiv.). The resulting solution was stirred at room temperature for eight hr and filtered through a bed of silica gel. The product is obtained in the form of a white solid after HPLC a preparatory scale
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Este ejemplo ilustra la preparación de 5-(4-toluenosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (4-toluenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
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El compuesto del título se preparó de una manera
similar al Ejemplo 3, comenzando con cloruro de
p-toluenosulfo-
nilo, o se puede adquirir de
Maybridge Chemical Co.The title compound was prepared in a manner similar to Example 3, starting with p- toluenesulfo-
Nile, or can be purchased from Maybridge Chemical Co.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 1,14 (3H, t); 2,39 (3H, s); 4,17 (2H, q); 7,10 (1H, d); 7,19 (1H, d); 7,33 (2H, d); 7,40 (1H, m); 7,66-7,69 (3H, m); 8,05 (1H, d); 8,23 (1H, d); 8,25(1H, s).1 H NMR (400 MHz) (CD 3 OD) δ 1.14 (3H, t); 2.39 (3H, s); 4.17 (2H, q); 7.10 (1H, d); 7.19 (1H, d); 7.33 (2H, d); 7.40 (1 H, m); 7.66-7.69 (3H, m); 8.05 (1H, d); 8.23 (1H, d); 8.25 (1H, s).
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 5-(4-(4-clorobenceno-sulfonamido)fenoxi)-3-cloropiridina.This example (not of the claimed invention) illustrates the preparation of 5- (4- (4-Chlorobenzene-sulfonamido) phenoxy) -3-chloropyridine.
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A una solución agitada de 4-fluoro-nitrobenceno (913 \muL, 8,61 mmoles, de Aldrich) en dioxano (1 mL) se le añadió 3-cloro-5-hidroxipiridina (558 mg, 4,31 mmoles, de Aldrich) seguido de trietilamina (661 \muL, 4,74 mmoles). La solución se sometió a reflujo durante 4,5 horas, se evaporó y el sólido bruto se disolvió en acetato de etilo. La solución se lavó tres veces con una solución saturada de K_{2}CO_{3}, una vez con salmuera y después se volvió a extraer con acetato de etilo. Las dos soluciones orgánicas se combinaron, se concentraron y el residuo se purificó mediante cromatografía (éter dietílico como eluyente) para proporcionar 481 mg del compuesto del título.To a stirred solution of 4-fluoro-nitrobenzene (913 µL, 8.61 mmol, from Aldrich) in dioxane (1 mL) was added 3-chloro-5-hydroxypyridine (558 mg, 4.31 mmol, from Aldrich) followed by triethylamine (661 µL, 4.74 mmol). The solution was refluxed for 4.5 hours, it was evaporated and the crude solid was dissolved in acetate ethyl. The solution was washed three times with a saturated solution of K 2 CO 3, once with brine and then extracted again with ethyl acetate. The two organic solutions were combined, they were concentrated and the residue was purified by chromatography (diethyl ether as eluent) to provide 481 mg of title compound.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 7,24 (2H, dd); 7,74 (1H, m); 8,32 (2H, dd); 8,39 (1H, m); 8,48 (1H, m).1 H NMR (400 MHz) (CD 3 OD) δ 7.24 (2H, dd); 7.74 (1 H, m); 8.32 (2H, dd); 8.39 (1 H, m); 8.48 (1H, m).
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A una solución agitada de 5-(4-nitrofenoxi)-3-cloropiridina (219 mg, 0,873 mmoles) en EtOH (4 mL) se le añadió SnCl_{2} (730 mg, 3,24 mmoles). La solución se sometió a reflujo durante 1,25 hr y el disolvente se eliminó mediante evaporación. El sólido bruto resultante se purificó mediante cromatografía (97,5:2,5 CH_{2}Cl_{2}:MeOH) para proporcionar 187,7 mg (78% rendimiento) del compuesto del título.To a stirred solution of 5- (4-nitrophenoxy) -3-chloropyridine (219 mg, 0.873 mmol) in EtOH (4 mL) SnCl2 (730) was added mg, 3.24 mmol). The solution was refluxed for 1.25 hr and The solvent was removed by evaporation. The gross solid The resulting was purified by chromatography (97.5: 2.5 CH 2 Cl 2: MeOH) to provide 187.7 mg (78% yield) of the title compound.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 6,69 (2H, dd); 6,86 (2H, dd); 7,14 (1H, m); 8,21 (2H, m).1 H NMR (400 MHz) (CDCl 3) δ 6.69 (2H, dd); 6.86 (2H, dd); 7.14 (1 H, m); 8.21 (2H, m).
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A una solución agitada de 5-(4-aminofenoxi)-3-cloropiridina (150 mg, 60,7 mmoles) en THF (2 mL) y MeOH (2 mL) se le añadió cloruro de 4-clorosulfonilo (215 mg, 1,02 mmoles) seguido de trietilamina (142 \muL, 1,02 mmoles). La solución se agitó durante siete hr, y se concentró. El sólido bruto se disolvió en acetato de etilo y se lavó tres veces con una solución saturada de K_{2}CO_{3}, una vez con salmuera, y después se volvió a extraer con acetato de etilo. Las porciones orgánicas se combinaron, se concentraron y el residuo se purificó mediante cromatografía (50:50, hexano:éter dietílico como eluyente) para proporcionar 178,7 mg (51%) del compuesto del título.To a stirred solution of 5- (4-aminophenoxy) -3-chloropyridine (150 mg, 60.7 mmol) in THF (2 mL) and MeOH (2 mL) was added 4-chlorosulfonyl chloride (215 mg, 1.02 mmol) followed by triethylamine (142 µL, 1.02 mmol). The solution is stirred for seven hr, and concentrated. The crude solid dissolved in ethyl acetate and washed three times with a saturated solution of K 2 CO 3, once with brine, and then returned to extract with ethyl acetate. The organic portions were combined, they were concentrated and the residue was purified by chromatography (50:50, hexane: diethyl ether as eluent) to provide 178.7 mg (51%) of the title compound.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 6,97 (2H, d); 7,15 (2H,d); 7,32 (1H, m); 7,48 (2H, d); 7,72 (2H, d); 8,15 (1H, s); 8,25 (1H, s).1 H NMR (400 MHz) (CDCl 3) δ 6.97 (2H, d); 7.15 (2H, d); 7.32 (1 H, m); 7.48 (2H, d); 7.72 (2H, d); 8.15 (1H, s); 8.25 (1H, s).
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(Tabla pasa a página siguiente)(Table goes to page next)
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Los compuestos de las Tablas B y C se prepararon utilizando métodos y condiciones similares a las proporcionadas en los Ejemplos 9-15, con las sustancias de partida apropiadas.The compounds of Tables B and C were prepared using methods and conditions similar to those provided in Examples 9-15, with the starting substances appropriate.
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Este ejemplo ilustra la preparación de N-etilo 5-(4-yodobencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of N-ethyl 5- (4-Iodobenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzamide.
El ácido 2-cloro-5-nitrobenzoico (20 g, 100 mmoles) en THF (200 mL) se trató con carbonildiimidazol (CDI) (17,8 g, 110 mmoles) y trietilamina (16 mL, 110 mmoles) a temperatura ambiente. Al cabo de 1 hr, se añadió una solución de etilamina (70% en agua, 10 mL) y la mezcla se agitó durante 18 h. El disolvente se eliminó mediante evaporación y el residuo se disolvió en cloruro de metileno, se lavó con una solución de KOH al 3% seguido de agua (tres veces) hasta que los extractos de la fase acuosa fueron incoloros. La fase orgánica se secó sobre MgSO_{4}, se filtró, y el producto filtrado se concentró para proporcionar 10,4 g de N-etil-2-cloro-5-nitrobenzamida en forma de cristales de color amarillo claro.Acid 2-chloro-5-nitrobenzoic (20 g, 100 mmol) in THF (200 mL) was treated with carbonyldiimidazole (CDI) (17.8 g, 110 mmol) and triethylamine (16 mL, 110 mmol) at room temperature. After 1 hr, a solution of ethylamine (70% in water, 10 mL) and the mixture was stirred for 18 h. He solvent was removed by evaporation and the residue was dissolved in methylene chloride, washed with a 3% KOH solution followed by water (three times) until the phase extracts Watery were colorless. The organic phase was dried over MgSO4, was filtered, and the filtrate was concentrated to provide 10.4 g of N-ethyl-2-chloro-5-nitrobenzamide in the form of light yellow crystals.
Alternativamente, el cloruro de 2-cloro-5-nitrobenzoilo (10 g, 45,5 mmoles) en diclorometano anhidro (250 mL) con resina de intercambio iónico Amberlyst A-21 (17 g) se trató con una solución en THF 2M de etilamina (45 mL). La mezcla se agitó a rt en nitrógeno durante la noche. Después de la filtración, el producto filtrado se concentró para dar N-etil-2-cloro-5-nitrobenzamida (9,0 g, 39 mmoles, rendimiento 86%) en forma de un sólido de color amarillo.Alternatively, the chloride of 2-chloro-5-nitrobenzoyl (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with resin Amberlyst A-21 ion exchange (17 g) was treated with a solution in 2M THF of ethylamine (45 mL). The mixture was stirred. to rt in nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) in the form of a colored solid yellow.
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A una suspensión de t-butóxido de potasio (1,5 g) en THF (15 mL) se le añadió 3-cloro-5-hidroxipiridina (1,79 g, mmoles). A esta solución se le añadió una solución de N-etil-2-cloro-5-nitrobenzamida (2,76 g, mmoles) en THF (15 mL). La mezcla resultante se calentó a 50ºC durante 84 hr. Después de enfriar, la mezcla de reacción se diluyó en una mezcla de agua y éter. Los sólidos se recogieron mediante filtración, se lavaron con agua, después con éter, y se secaron a vacío para proporcionar N-etil-5-nitro-2-(3-cloro-5-piridiloxi)benzamida (2,0 g, 52%). pf 165-167ºC.To a suspension of t-butoxide Potassium (1.5 g) in THF (15 mL) was added 3-chloro-5-hydroxypyridine (1.79 g, mmol). To this solution was added a solution of N-ethyl-2-chloro-5-nitrobenzamide (2.76 g, mmol) in THF (15 mL). The resulting mixture was heated to 50 ° C for 84 hr. After cooling, the reaction mixture is diluted in a mixture of water and ether. The solids were collected by filtration, washed with water, then with ether, and vacuum dried to provide N-ethyl-5-nitro-2- (3-chloro-5-pyridyloxy) benzamide (2.0 g, 52%). mp 165-167 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 8,544 (s, 2H); 8,476 (s, 1H); 8,436 (s, 1H); 8,303 (d, J=9 Hz, 1H); 7,860 (s, 1H); 7,247 (d, J= 8,9 Hz, 1H); 3,241 (p, J= 6,5 Hz, 2H); 1,047 (t, J= 7,0 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 8.544 (s, 2H); 8,476 (s, 1 H); 8.436 (s, 1 H); 8.303 (d, J = 9 Hz, 1H); 7,860 (s, 1 H); 7.247 (d, J = 8.9 Hz, 1H); 3,241 (p, J = 6.5 Hz, 2H); 1,047 (t, J = 7.0 Hz, 3H).
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A una solución agitada vigorosamente del intermedio del Ejemplo 17,2 (2,47 g) en etanol (100 mL) y THF (20 mL) en un matraz de fondo redondo de 500 mL se le añadió una suspensión de Níquel Raney (\sim100 mg, Aldrich). El matraz se cargó con H_{2} a presión atmosférica y la reducción se verificó mediante TLC. La sustancia de partida desapareció rápidamente, para formar un intermedio nitroso que se convirtió gradualmente en la anilina deseada a lo largo de aproximadamente 5 horas. Se detuvo la agitación y se atrajo tanto Níquel Raney como fue posible a la varilla agitadora magnética. La solución se filtró a través de Celite® que después se enjuagó con etanol y cloruro de metileno. Las porciones orgánicas combinadas se concentraron para proporcionar un sólido que se trituró con éter. El sólido se recogió y se secó a vacío para proporcionar 2,02 g de la anilina producto. pf 126-128ºC.To a vigorously stirred solution of intermediate of Example 17.2 (2.47 g) in ethanol (100 mL) and THF (20 mL) in a 500 mL round bottom flask was added a Raney Nickel suspension (? 100 mg, Aldrich). The flask is charged with H2 at atmospheric pressure and the reduction was verified by TLC. The starting substance disappeared quickly, to form a nitrous intermediate that gradually became the desired aniline over approximately 5 hours. He stopped the agitation and attracted as much nickel raney as possible to the magnetic stirring rod. The solution was filtered through Celite® which was then rinsed with ethanol and methylene chloride. The combined organic portions were concentrated to provide a solid that was triturated with ether. The solid was collected and dried at vacuum to provide 2.02 g of the product aniline. pf 126-128 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 8,260 (s, 1H); 8,180 (s, 1H); 8,146 (t, J=5,2 Hz, 1H); 7,230 (t, J= 2,3 Hz, 1H); 6,872 (t, J= 7,7 Hz, 1H); 6,749 (d, J= 2,7 Hz, 1H); 6,668 (dd, J= 8,6, 2,7 Hz, 1H); 3,073 (p, J= 7,1 Hz, 2H); 0,881 (t, J= 6,6 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 8.260 (s, 1H); 8,180 (s, 1 H); 8.146 (t, J = 5.2 Hz, 1H); 7.230 (t, J = 2.3 Hz, 1H); 6.872 (t, J = 7.7 Hz, 1H); 6.749 (d, J = 2.7 Hz, 1H); 6.668 (dd, J = 8.6, 2.7 Hz, 1H); 3,073 (p, J = 7.1 Hz, 2H); 0.881 (t, J = 6.6 Hz, 3H).
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A una suspensión de N-etil-5-amino-2-(3-cloro-5-piridiloxi)benzamida del Ejemplo 17,3 (0,9 g) en cloruro de metileno (10 mL) se le añadió cloruro de 4-yodobencenosulfonilo (1,03 g), seguido de piridina (275 \muL). El progreso de la reacción se verificó mediante TLC, y tras su terminación el disolvente se eliminó a vacío. El residuo resultante se repartió entre cloruro de metileno y agua. La capa orgánica se retiró y se concentró para formar cristales de color rosa. Los cristales se disolvieron en acetato de etilo (200 mL) y metanol (10 mL), y se decoloraron con carbón activado. Después de la filtración, la solución se concentró hasta un aceite y el residuo se trituró con éter para proporcionar 1,26 g del compuesto del título en forma de cristales incoloros. pf 154-156ºC.To a suspension of N-ethyl-5-amino-2- (3-chloro-5-pyridyloxy) benzamide of Example 17.3 (0.9 g) in methylene chloride (10 mL) was added 4-iodobenzenesulfonyl chloride (1.03 g), followed by pyridine (275 µL). The progress of the reaction is verified by TLC, and after completion the solvent was Vacuum removed. The resulting residue was partitioned between methylene and water. The organic layer was removed and concentrated to form pink crystals. The crystals dissolved in ethyl acetate (200 mL) and methanol (10 mL), and were discolored with activated carbon. After filtration, the solution was concentrated. to an oil and the residue was triturated with ether to provide 1.26 g of the title compound as colorless crystals. pf 154-156 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 9,393 (s, 1H); 8,578 (br s, 1H); 8,462 (br s, 1H); 8,256 (d, J= 2,2 Hz, 1H); 7,915 (d, J= 7,7 Hz, 2H); 7,774 (dd, J= 8,9, 1,8 Hz, 1H); 7,665 (d, J= 7,7 Hz, 2H); 7,566 (t, J= 5,3 Hz, 1H, NH); 7,418 (br s, 1H); 6,966 (d, J= 8,8 Hz, 2H); 3,722 (p, J= 6,8 Hz, 2H); 1,323 (t, J= 6,6 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 9.393 (s, 1H); 8,578 (br s, 1 H); 8,462 (br s, 1 H); 8.256 (d, J = 2.2 Hz, 1H); 7,915 (d, J = 7.7 Hz, 2H); 7.774 (dd, J = 8.9, 1.8 Hz, 1H); 7.665 (d, J = 7.7 Hz, 2H); 7.566 (t, J = 5.3 Hz, 1H, NH); 7.418 (br s, 1 H); 6,966 (d, J = 8.8 Hz, 2H); 3.722 (p, J = 6.8 Hz, 2H); 1,323 (t, J = 6.6 Hz, 3H).
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A una suspensión del compuesto producido en el Ejemplo 17,4 (1,23 g) en metanol (15 mL) se le añadió 1 eq de una solución de NaOH (2,23 mL 0,99N). Se produjo la disolución completa y el disolvente se eliminó a vacío. El aceite resultante se disolvió in 11 mL de acetonitrilo 20% en agua y se liofilizó para proporcionar 1,33 g del compuesto del título en forma de un monohidrato de la sal de sodio.To a suspension of the compound produced in the Example 17.4 (1.23 g) in methanol (15 mL) was added 1 eq of a NaOH solution (2.23 mL 0.99N). The complete dissolution occurred and the solvent was removed in vacuo. The resulting oil is dissolved in 11 mL of 20% acetonitrile in water and lyophilized to provide 1.33 g of the title compound as a sodium salt monohydrate.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 8,381 (s, 1H); 8,300 (s, 1H); 8,182 (br s, 1H); 7,867 (d, J= 7,7 Hz, 2H); 7,615 (dd, J= 8,9, 1,8 Hz, 1H); 7,327 (s, 1H); 7,055 (s, 1H); 7,038 (m, 1H); 6,877 (d, J= 8,8 Hz, 1H); 3,193 (p, J= 6,8 Hz, 2H); 1,006 (t, J= 6,8 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 8.381 (s, 1H); 8,300 (s, 1 H); 8,182 (br s, 1 H); 7.867 (d, J = 7.7 Hz, 2H); 7.615 (dd, J = 8.9, 1.8 Hz, 1H); 7.327 (s, 1 H); 7.055 (s, 1 H); 7.038 (m, 1 H); 6.877 (d, J = 8.8 Hz, 1H); 3.193 (p, J = 6.8 Hz, 2H); 1.006 (t, J = 6.8 Hz, 3H).
C_{20}H_{16}N_{3}ISO_{4}ClNa\cdotH_{2}O calc: %C 40,18 %H 3,04 %N 7,03 encontrado: %C 40,45 %H 2,89 %N 6,99.C_ {20} H_ {16} N_ {3} ISO_ {4} ClNa \ cdotH_ {O} calc:% C 40.18% H 3.04% N 7.03 found:% C 40.45% H 2.89% N 6.99.
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Los compuestos de la Tabla D se prepararon utilizando métodos similares a los proporcionados en el Ejemplo 17, sustituyendo el fenol apropiado, naftol, piridinol o quinolinol durante 5-cloro-3-piridinol, y sustituyendo cloruro de 2,4-dicloro-5-metilbencenosulfonilo por cloruro de 4-yodobencenosulfonilo.The compounds of Table D were prepared using methods similar to those provided in Example 17, substituting the appropriate phenol, naphthol, pyridinol or quinolinol during 5-chloro-3-pyridinol, and replacing chloride of 2,4-dichloro-5-methylbenzenesulfonyl by 4-iodobenzenesulfonyl chloride.
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Este ejemplo ilustra la preparación de N-etil-5-(4-metoxibencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of N-ethyl-5- (4-methoxybenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzamide.
La anilina producida en el Ejemplo 17,3 (0,42 g) se combinó con cloruro de 4-metoxibencenosulfonilo (0,297 g) en las condiciones proporcionadas en el Ejemplo 17,4 para proporcionar 0,3 g del compuesto del título en forma de un producto cristalino después de la cromatografía instantánea. pf 146-147ºC.The aniline produced in Example 17.3 (0.42 g) was combined with 4-methoxybenzenesulfonyl chloride (0.297 g) under the conditions provided in Example 17.4 for provide 0.3 g of the title compound as a product crystalline after instant chromatography. pf 146-147 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 10,319 (s, 1H); 8,359 (d, J=1,9 Hz, 1H); 8,262 (t, J=5,6 Hz, 1H); 8,213 (d, J= 2,2 Hz, 1H); 7,700 (d, J=8,4 Hz, 2H); 7,383 (t, J=2,4 Hz, 1H); 7,292 (d, J=2,4 Hz, 1H); 7,192 (dd, J= 8,8, 2,4 Hz, 1H); 7,077 (d, J= 8,8 Hz, 1H); 7,040 (d, J=8,8 Hz, 1H); 3,806 (s, 3H); 3,105 (p, J= 7 Hz, 2H); 0,901 (t, J= 7,2 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 10.319 (s, 1H); 8.359 (d, J = 1.9 Hz, 1H); 8.262 (t, J = 5.6 Hz, 1H); 8.213 (d, J = 2.2 Hz, 1H); 7,700 (d, J = 8.4 Hz, 2H); 7.383 (t, J = 2.4 Hz, 1H); 7.292 (d, J = 2.4 Hz, 1H); 7.192 (dd, J = 8.8, 2.4 Hz, 1H); 7.077 (d, J = 8.8 Hz, 1H); 7.040 (d, J = 8.8 Hz, 1H); 3,806 (s, 3 H); 3.105 (p, J = 7 Hz, 2H); 0.901 (t, J = 7.2 Hz, 3H).
C_{21}H_{20}N_{3}SO_{5}Cl calc: %C 54,60 %H 4,36 %N 9,10 encontrado: %C 54,38 %H 4,36 %N 8,95.C 21 H 20 N 3 SO 5 Cl calc:% C 54.60 % H 4.36% N 9.10 found:% C 54.38% H 4.36% N 8.95.
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Los compuestos proporcionados en la Tabla E se prepararon utilizando los métodos descritos en el Ejemplo 17 y el cloruro de arilsulfonilo apropiado.The compounds provided in Table E are prepared using the methods described in Example 17 and the appropriate arylsulfonyl chloride.
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Este ejemplo ilustra la preparación de 5-(5-trifluorometil-2-piridinosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (5-Trifluoromethyl-2-pyridinosulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
Una solución de ácido 2-cloro-5-nitrobenzoico (26 g) en etanol (260 mL) y ácido sulfúrico concentrado (1 mL) se calentó a reflujo durante 18 hr. La mezcla de reacción se enfrió y se añadió K_{2}CO_{3} para sofocar la reacción. La mezcla resultante se filtró y se concentró. El residuo se suspendió después en éter y se filtró para eliminar el ácido de partida insoluble. El producto filtrado se lavó con KOH al 4% (110 mL), se secó sobre MgSO_{4} y se concentró para proporcionar 16,2 g de 2-cloro-5-nitrobenzoato de etilo en forma de un aceite incoloro que se solidificó al reposar.An acid solution 2-chloro-5-nitrobenzoic (26 g) in ethanol (260 mL) and concentrated sulfuric acid (1 mL) are heated to reflux for 18 hr. The reaction mixture was cooled and K2CO3 was added to quench the reaction. Mix The resulting was filtered and concentrated. The residue was suspended after in ether and filtered to remove insoluble starting acid. He Filtrate was washed with 4% KOH (110 mL), dried over MgSO 4 and concentrated to provide 16.2 g of 2-chloro-5-nitrobenzoate of ethyl in the form of a colorless oil that solidified by rest.
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A una solución del éster del Ejemplo 21.1 (3 g) y 3-cloro-5-hidroxipiridina (1,79 g) en DMF (20 mL) se le añadieron 2 g de K_{2}CO_{3}. La mezcla resultante se calentó a 50ºC y el progreso de la reacción se verificó mediante TLC. Al finalizar, la mezcla de reacción se diluyó en agua y se extrajo con éter. La fase orgánica se secó sobre MgSO_{4}, se filtró y se concentró para dar 4,19 g del compuesto del título.To an ester solution of Example 21.1 (3 g) Y 3-chloro-5-hydroxypyridine (1.79 g) in DMF (20 mL) 2 g of K 2 CO 3 were added. The resulting mixture was heated to 50 ° C and the progress of the reaction was verified by TLC. Upon completion, the reaction mixture is diluted in water and extracted with ether. The organic phase dried over MgSO4, filtered and concentrated to give 4.19 g of title compound.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,904 (d, J=2,8 Hz, 1H); 8,508 (d, J=1,9 Hz, 1H); 8,459 (dd, J= 7,6, 2,8 Hz, 1H); 8,399 (d, J= 2,5 Hz, 1H); 7,447 (t, J=2,3 Hz, 1H); 7,220 (d, J=9 Hz, 1H) 4,451 (q, J= 7,2 Hz, 2H); 1,411 (t, J= 7,2 Hz, 3H)1 H NMR (400 MHz) (CDCl 3) δ 8.904 (d, J = 2.8 Hz, 1H); 8.508 (d, J = 1.9 Hz, 1H); 8.459 (dd, J = 7.6, 2.8 Hz, 1H); 8.399 (d, J = 2.5 Hz, 1H); 7.447 (t, J = 2.3 Hz, 1H); 7.220 (d, J = 9 Hz, 1H) 4,451 (q, J = 7.2 Hz, 2H); 1,411 (t, J = 7.2 Hz, 3H)
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Utilizando el método descrito en el Ejemplo 17.3, el producto del Ejemplo 21.2 (4,1 g) en etanol (120 mL) se convirtió en 5-amino-2-(3-cloro-5-piridiloxi)benzoato de etilo (1,79 g, pf 110-112ºC).Using the method described in the Example 17.3, the product of Example 21.2 (4.1 g) in ethanol (120 mL) is turned into 5-amino-2- (3-chloro-5-pyridyloxy) benzoate ethyl (1.79 g, mp 110-112 ° C).
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 8,250 (s, 1H); 8,142 (s, 1H); 7,192 (s, 1H); 7,113 (s, 1H); 6,979 (d, J= 8,4 Hz, 1H); 6,834 (d, J= 8,6 Hz, 1H); 5,466 (s, 2H); 4,078 (q, J= 7 Hz, 2H); 1,0091 (t, J= 7 Hz, 3H)1 H NMR (400 MHz) (DMSO-d 6) δ 8.250 (s, 1H); 8.142 (s, 1 H); 7.192 (s, 1 H); 7.113 (s, 1 H); 6,979 (d, J = 8.4 Hz, 1H); 6.834 (d, J = 8.6 Hz, 1H); 5,466 (s, 2 H); 4,078 (q, J = 7 Hz, 2H); 1.0091 (t, J = 7 Hz, 3H)
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La 5-trifluorometil-2-cloropiridina (14,75 g) se convirtió en 5-trifluorometil-2-piridinotiol (7,12 g, pf 165-167ºC) mediante el método de Lansbury (J. Amer. Chem. Soc., 92: 5649 (1970)).The 5-trifluoromethyl-2-chloropyridine (14.75 g) became 5-trifluoromethyl-2-pyridinothiol (7.12 g, mp 165-167 ° C) by the method of Lansbury (J. Amer. Chem. Soc., 92: 5649 (1970)).
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El piridinotiol del Ejemplo 21,4 se convirtió en el cloruro de sulfonilo correspondiente utilizando el método de Fors, et al., J. Org. Chem. 63:7348 (1998). En pocas palabras, el piridinotiol (3,5 g) se suspendió en HCl 1M (53 mL) y se enfrió en hielo. Se hizo burbujear gas cloro en el matraz de reacción tarado hasta que se hubieron añadido 3 eq (4,2 g). El sólido de color blanco resultante se disolvió en cloruro de metileno frío (25 mL) y se extrajo de la solución de HCl. La capa acuosa se lavó con 12,5 mL adicionales de cloruro de metileno. La presencia de cloro activo se verificó mediante una solución de KI y se añadió isopreno (800 \muL) para descomponer el cloro residual. Se obtuvieron un total de 37,5 g de solución de cloruro de sulfonilo en cloruro de metileno. La titulación aproximativa de esta solución con una anilina mostró una concentración efectiva de aproximadamente 0,15 g/mL. La solución titulada se mantuvo fría (hielo seco) hasta que se usó.The pyridinothiol of Example 21.4 was converted to the corresponding sulfonyl chloride using the method of Fors, et al ., J. Org. Chem. 63: 7348 (1998). Simply put, pyridinothiol (3.5 g) was suspended in 1M HCl (53 mL) and cooled on ice. Chlorine gas was bubbled into the tared reaction flask until 3 eq (4.2 g) had been added. The resulting white solid was dissolved in cold methylene chloride (25 mL) and extracted from the HCl solution. The aqueous layer was washed with an additional 12.5 mL of methylene chloride. The presence of active chlorine was verified by a solution of KI and isoprene (800 µL) was added to decompose the residual chlorine. A total of 37.5 g of sulfonyl chloride solution in methylene chloride were obtained. Approximate titration of this solution with an aniline showed an effective concentration of approximately 0.15 g / mL. The titled solution was kept cold (dry ice) until it was used.
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De una manera similar al Ejemplo 17,4, la anilina producida en el Ejemplo 21,3 (0,23 g) se recogió en cloruro de metileno (2,5 mL) y piridina (0,25 mL), y se trató con 1,5 mL de la solución del Ejemplo 21,5. Después de la cromatografía instantánea y la trituración con éter, se obtuvo la sulfonamida del título (58 mg). pf 133-135ºC.In a manner similar to Example 17.4, the aniline produced in Example 21.3 (0.23 g) was taken up in chloride of methylene (2.5 mL) and pyridine (0.25 mL), and treated with 1.5 mL of the solution of Example 21.5. After chromatography instantaneous and trituration with ether, sulfonamide was obtained from titer (58 mg). mp 133-135 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 11,106 (s, 1H); 9,190 (dd, J=1,6, 0,8 Hz, 1H); 8,524 (dd, J=8, 2,4 Hz, 1H); 8,333 (d, J= 2 Hz, 1H); 8,168 (t, J=2,8 Hz, 1H); 7,689 (d, J=2,8 Hz, 1H); 7,460 (dd, J=8,8, 3,2 Hz, 1H); 7,345 (t, J= 2 Hz, 1H); 4,116 (q, J= 7,2 Hz, 2H); 1,037 (t, J= 7,2 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 11.106 (s, 1H); 9.190 (dd, J = 1.6, 0.8 Hz, 1H); 8.524 (dd, J = 8, 2.4 Hz, 1H); 8.333 (d, J = 2 Hz, 1H); 8.168 (t, J = 2.8 Hz, 1H); 7.689 (d, J = 2.8 Hz, 1H); 7.460 (dd, J = 8.8, 3.2 Hz, 1H); 7.345 (t, J = 2 Hz, 1H); 4,116 (q, J = 7.2 Hz, 2H); 1,037 (t, J = 7.2 Hz, 3H).
C_{20}H_{15}N_{3}F_{3}SO_{5}Cl calc: %C 47,87 %H 3,01 %N 8,37 encontrado: %C 47,93 %H 3,00 %N 8,30.C 20 H 15 N 3 F 3 SO 5 Cl calc: % C 47.87% H 3.01% N 8.37 found:% C 47.93% H 3.00% N 8.30.
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Este ejemplo ilustra la preparación de 5-(2,4-diclorobenceno-sulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (2,4-Dichlorobenzene-sulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
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La anilina producida en el Ejemplo 21,3 (1,5 g)
se convirtió en el compuesto del título utilizando cloruro de
2,4-diclorobencenosulfonilo (1,26 g) de una manera
similar a la descrita en el Ejemplo 17.4. El compuesto del título
(1,99 g) se obtuvo en forma de un producto cristalino después de la
cromatografía instantánea y la trituración con
hexano.The aniline produced in Example 21.3 (1.5 g) was converted to the title compound using 2,4-dichlorobenzenesulfonyl chloride (1.26 g) in a manner similar to that described in Example 17.4. The title compound (1.99 g) was obtained as a crystalline product after flash chromatography and trituration with
hexane
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,279 (br s, 1H); 8,131 (br s, 1H); 7,966 (d, J= 8,7 Hz, 1H); 7,669 (d, J= 2,8 Hz, 1H); 7,560 (d, J= 1,9 Hz, 1H); 7,381 (m, 2H); 7,159 (br s, 1H); 7,081 (t, J=1,9 Hz, 2H); 6,979 (d, J=8 Hz, 1H); 4,221 (q, J= 7 Hz, 2H); 1,175 (t, J= 7Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.279 (br s, 1H); 8,131 (br s, 1 H); 7,966 (d, J = 8.7 Hz, 1H); 7.669 (d, J = 2.8 Hz, 1H); 7.560 (d, J = 1.9 Hz, 1H); 7.381 (m, 2H); 7,159 (br s, 1 H); 7.081 (t, J = 1.9 Hz, 2H); 6,979 (d, J = 8 Hz, 1H); 4,221 (q, J = 7 Hz, 2H); 1,175 (t, J = 7Hz, 3H).
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Los compuestos proporcionados en la Tabla F se prepararon utilizando los métodos descritos en el Ejemplo 22 y el cloruro de arilsulfonilo apropiado.The compounds provided in Table F are prepared using the methods described in Example 22 and the appropriate arylsulfonyl chloride.
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Este ejemplo ilustra la preparación de 5-(6-cloro-3-piridinosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (6-Chloro-3-pyridinosulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
La anilina producida en el Ejemplo 21,3 se convirtió en el compuesto del título utilizando cloruro de 2-cloropiridino-5-sulfonilo de una manera similar a la descrita en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino después de la cromatografía instantánea y la trituración con hexano. pf 166-168ºC.The aniline produced in Example 21.3 is became the title compound using chloride 2-chloropyridino-5-sulfonyl in a manner similar to that described in Example 17.4. He title compound was obtained in the form of a crystalline product after instant chromatography and crushing with hexane. mp 166-168 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,827 (s, 1H); 8,745 (d, J= 2,6 Hz, 1H); 8,341 (d, J= 1,8 Hz, 1H); 8,184 (d, J= 2,6 Hz, 2H); 8,152 (dd, J= 8,4, 2,6 Hz, 1H); 7,762 (d, J=8,4 Hz, 1H); 7,62 (d, J=2,7 Hz, 1H); 7,397 (dd, J=8,6, 2,8 Hz, 1H); 7,381 (d, J=1,1 Hz, 1H); 7,269 (d, J=8,8 Hz, 1H); 4,121 (q, J= 7 Hz, 2H); 1,043 (t, J= 7,1 Hz,, 3H).1 H NMR (400 MHz) (CDCl 3) δ 10.827 (s, 1H); 8.745 (d, J = 2.6 Hz, 1H); 8.341 (d, J = 1.8 Hz, 1H); 8.184 (d, J = 2.6 Hz, 2H); 8.152 (dd, J = 8.4, 2.6 Hz, 1H); 7.762 (d, J = 8.4 Hz, 1H); 7.62 (d, J = 2.7 Hz, 1H); 7.397 (dd, J = 8.6, 2.8 Hz, 1H); 7.381 (d, J = 1.1 Hz, 1H); 7.269 (d, J = 8.8 Hz, 1H); 4,121 (q, J = 7 Hz, 2H); 1,043 (t, J = 7.1 Hz ,, 3H).
C_{19} H_{15}N_{3}Cl_{2}SO_{5} calc: %C 48,73 %H 3,23 %N 8,97 encontrado: %C 48,49 %H 3,33 %N 8,71.C 19 H 15 N 3 Cl 2 SO 5 calc: % C 48.73% H 3.23% N 8.97 found:% C 48.49% H 3.33% N 8.71.
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Este ejemplo ilustra la preparación de 5-(3-piridinosulfonamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the preparation of 5- (3-pyridinosulfonamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
La anilina producida en el Ejemplo 21,3 se convirtió en el compuesto del título utilizando cloruro de piridino-3-sulfonilo de una manera similar a la descrita en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino después de la cromatografía instantánea y la trituración con acetato de etilo/hexano. pf 120-122ºC.The aniline produced in Example 21.3 is became the title compound using chloride pyridino-3-sulfonyl in one way similar to that described in Example 17.4. The title compound is obtained in the form of a crystalline product after the instant chromatography and trituration with acetate ethyl / hexane. mp 120-122 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,775 (s, 1H); 8,906 (d, J= 1,8 Hz, 1H); 8,817 (d, J= 1,6 Hz, 1H); 8,334 (d, J= 2,1 Hz, 1H); 8,159 (d, J= 2,5 Hz, 1H); 8,138 (ddd, J= 8,1, 2,4, 1,1 Hz, 1H); 7,630 (ddd, J= 8,1, 4,8, 1,1 Hz, 1H); 7,623 (d, J= 2,9 Hz, 1H); 7,393 (dd, J= 8,8, 2,8 Hz, 1H); 7,358 (d, J=2,3 Hz, 1H); 7,228 (d, J=8,8 Hz, 1H); 4,113 (q, J= 7,2 Hz, 2H); 1,035 (t, J= 7,1 Hz,, 3H).1 H NMR (400 MHz) (CDCl 3) δ 10.775 (s, 1H); 8,906 (d, J = 1.8 Hz, 1H); 8.817 (d, J = 1.6 Hz, 1H); 8.334 (d, J = 2.1 Hz, 1H); 8.159 (d, J = 2.5 Hz, 1H); 8.138 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H); 7.630 (ddd, J = 8.1, 4.8, 1.1 Hz, 1H); 7.623 (d, J = 2.9 Hz, 1H); 7.393 (dd, J = 8.8, 2.8 Hz, 1H); 7.358 (d, J = 2.3 Hz, 1H); 7.228 (d, J = 8.8 Hz, 1H); 4,113 (q, J = 7.2 Hz, 2H); 1,035 (t, J = 7.1 Hz ,, 3H).
C_{19}H_{16}N_{3}ClSO_{5} calc: %C 52,60 %H 3,72 %N 9,68 encontrado: %C 52,54 %H 3,78 %N 9,40.C 19 H 16 N 3 ClSO 5 calc:% C 52.60 % H 3.72% N 9.68 found:% C 52.54% H 3.78% N 9.40.
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Este ejemplo ilustra la preparación de N-etil-5-(5-trifluorometil-2-piridinosulfonamido)-2-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of N-ethyl-5- (5-trifluoromethyl-2-pyridinosulfonamido) -2- (3-chloro-5-pyridyloxy) benzamide.
La anilina (56 mg) producida en el Ejemplo 17.3 se convirtió en el compuesto del título utilizando el cloruro de sulfonilo producido en el Ejemplo 21.5, de una manera similar a la descrita en el Ejemplo 21.6. El compuesto del título (33 mg) se obtuvo en forma de un producto cristalino. pf 147-148ºC.The aniline (56 mg) produced in Example 17.3 became the title compound using the chloride of sulfonyl produced in Example 21.5, in a manner similar to the described in Example 21.6. The title compound (33 mg) is obtained in the form of a crystalline product. pf 147-148 ° C.
RMN H^{1} (400 MHz) (DMSO-d_{6}) \delta 10,989 (s, 1H); 9,189 (s, 1H); 8,532 (d, J=8,4 Hz, 1H); 8,363 (d, J= 2,4 Hz, 1H); 8,278 (t, J=5,2 Hz, 1H); 8,229 (d, J=2,4 Hz, 1H); 8,193 (d, J=8 Hz, 1H); 7,416 (d, J=2 Hz, 1H); 7,350 (d, J= 2,8 Hz, 1H); 7,266 (dd, J=8,4, 2,4 Hz, 1H); 7,050 (d, J=8,8 Hz, 1H); 3,105 (p, J= 6,8 Hz, 2H); 0,904 (t, J= 6,8 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 10.989 (s, 1H); 9.189 (s, 1 H); 8.532 (d, J = 8.4 Hz, 1H); 8.363 (d, J = 2.4 Hz, 1H); 8.278 (t, J = 5.2 Hz, 1H); 8.229 (d, J = 2.4 Hz, 1H); 8.193 (d, J = 8 Hz, 1H); 7.416 (d, J = 2 Hz, 1H); 7.350 (d, J = 2.8 Hz, 1H); 7.266 (dd, J = 8.4, 2.4 Hz, 1H); 7.050 (d, J = 8.8 Hz, 1H); 3.105 (p, J = 6.8 Hz, 2H); 0.904 (t, J = 6.8 Hz, 3H).
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Este ejemplo ilustra la preparación de 5-(2,4-diclorofenilsulfonamido)-2-(3,5-difluorofenoxi)benzoato de etilo.This example illustrates the preparation of 5- (2,4-Dichlorophenylsulfonamido) -2- (3,5-difluorophenoxy) benzoate of ethyl.
Utilizando el método descrito en el Ejemplo 21.2, se combinaron 2-cloro-5-nitrobenzoato de etilo (0,6 g) y 3,5-difluorofenol (0,34 g) para proporcionar 0,8 g del compuesto del título.Using the method described in the Example 21.2, were combined 2-chloro-5-nitrobenzoate ethyl (0.6 g) and 3,5-difluorophenol (0.34 g) for provide 0.8 g of the title compound.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,955 (d, J=2,9 Hz, 1H); 8,497 (dd, J=9,1, 2,8 Hz, 1H); 7,272 (d, J= 9,2 Hz, 1H); 6,797 (dd, J=11, 8,8 Hz, 1H); 6,688 (dd, J=6,9, 1,4 Hz, 1H) 4,501 (q, J= 7 Hz, 2H); 1,465 (t, J= 7,1 Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.955 (d, J = 2.9 Hz, 1H); 8.497 (dd, J = 9.1, 2.8 Hz, 1H); 7.272 (d, J = 9.2 Hz, 1H); 6.797 (dd, J = 11, 8.8 Hz, 1H); 6.688 (dd, J = 6.9, 1.4 Hz, 1H) 4.501 (q, J = 7 Hz, 2H); 1,465 (t, J = 7.1 Hz, 3H).
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Utilizando el método del Ejemplo 17.3, el 5-nitro-2-(3,5-difluorofenoxi)benzoato de etilo (0,76 g) en etanol (7 mL) y THF (3 mL) se convirtió en el derivado de anilina correspondiente que se obtuvo en forma de un aceite (0,696 g).Using the method of Example 17.3, the 5-nitro-2- (3,5-difluorophenoxy) benzoate of ethyl (0.76 g) in ethanol (7 mL) and THF (3 mL) became the corresponding aniline derivative that was obtained in the form of a oil (0.696 g).
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 7,108 (d, J=2,9 Hz, 1H); 7,097 (s, 1H); 6,762 (d, J= 8,6 Hz, 1H); 6,692 (dd, J=8,6, 2,9 Hz, 1H); 6,263 (tt, J=9, 2,2 Hz, 1H); 6,182 (dd, J=8,7, 2,2 Hz, 1H); 4,037 (q, J= 7,2 Hz, 2H); 0,988 (t, J= 7,1 Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 7.108 (d, J = 2.9 Hz, 1H); 7.097 (s, 1 H); 6.762 (d, J = 8.6 Hz, 1H); 6.692 (dd, J = 8.6, 2.9 Hz, 1H); 6.263 (tt, J = 9, 2.2 Hz, 1H); 6.182 (dd, J = 8.7, 2.2 Hz, 1H); 4,037 (q, J = 7.2 Hz, 2H); 0.988 (t, J = 7.1 Hz, 3H).
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A la anilina producto del Ejemplo 27.2 (0,175 g) se le añadió cloruro de 2,4-diclorobencenosulfonilo ((0,149 g) en condiciones similares a las empleadas en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino (0,227 g) después de la cromatografía instantánea y la trituración con hexano. pf 100-102ºC.To the aniline product of Example 27.2 (0.175 g) 2,4-dichlorobenzenesulfonyl chloride was added ((0.149 g) under conditions similar to those used in the Example 17.4. The title compound was obtained in the form of a product. crystalline (0.227 g) after flash chromatography and the crushing with hexane. mp 100-102 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 7,973 (d, J=8,5 Hz, 1H); 7,664 (d, J=2,8 Hz, 1H); 7,567 (d, J= 1,9 Hz, 1H); 7,381 (m, 2H); 7,174 (br s, 1H); 6,997 (d, J=8,8 Hz, 2H); 6,502 (tt, J=8,9, 2,3 Hz, 1H); 6,324 (m, 2H); 4,232 (q, J= 7,2 Hz, 2H); 1,192 (t, J= 7,1 Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 7.973 (d, J = 8.5 Hz, 1H); 7.664 (d, J = 2.8 Hz, 1H); 7.567 (d, J = 1.9 Hz, 1H); 7.381 (m, 2H); 7.174 (br s, 1 H); 6,997 (d, J = 8.8 Hz, 2H); 6.502 (tt, J = 8.9, 2.3 Hz, 1H); 6.324 (m, 2H); 4,232 (q, J = 7.2 Hz, 2H); 1,192 (t, J = 7.1 Hz, 3H).
C_{21} H_{15}F_{2}Cl_{2}SNO_{5} calc: %C 50,21 %H 3,01 %N 2,79 encontrado: %C 50,46 %H 3,13 %N 2,82.C 21 H 15 F 2 Cl 2 SNO 5 calc: % C 50.21% H 3.01% N 2.79 found:% C 50.46% H 3.13% N 2.82.
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Este ejemplo ilustra la preparación de 5-(2,4-diclorobencenosulfonamido)-2-(3,4-difluorofenoxi)benzoato de etilo.This example illustrates the preparation of 5- (2,4-Dichlorobenzenesulfonamido) -2- (3,4-difluorophenoxy) benzoate of ethyl.
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Utilizando el método descrito en el Ejemplo 21.2, se combinaron 2-cloro-5-nitrobenzoato de etilo (0,6 g) y 3,4-difluorofenol (0,34 g) para proporcionar 0,8 g del compuesto del título en forma de un aceite.Using the method described in the Example 21.2, were combined 2-chloro-5-nitrobenzoate ethyl (0.6 g) and 3,4-difluorophenol (0.34 g) for provide 0.8 g of the title compound as a oil.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,772 (d, J=2,9 Hz, 1H); 8,288 (dd, J=9,1, 2,9 Hz, 1H); 7,206 (d, J= 8,9 Hz, 1H); 6,980 (d, J=9,2 Hz, 1H); 6,928 (ddd, J=10,6, 6,5, 2,9 Hz, 1H); 4,383 (q, J= 7,1 Hz, 2H); 1,358 (t, J= 7,1 Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.772 (d, J = 2.9 Hz, 1H); 8.288 (dd, J = 9.1, 2.9 Hz, 1H); 7.206 (d, J = 8.9 Hz, 1H); 6,980 (d, J = 9.2 Hz, 1H); 6,928 (ddd, J = 10.6, 6.5, 2.9 Hz, 1H); 4.383 (q, J = 7.1 Hz, 2H); 1,358 (t, J = 7.1 Hz, 3H).
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Utilizando el método del Ejemplo 17.3, el 5-nitro-2-(3,4-difluorofenoxi)benzoato de etilo (0,76 g) en etanol (8 mL) se convirtió en el derivado de anilina correspondiente que se obtuvo en forma de un aceite (0,67 g).Using the method of Example 17.3, the 5-nitro-2- (3,4-difluorophenoxy) benzoate of ethyl (0.76 g) in ethanol (8 mL) became the derivative of corresponding aniline that was obtained in the form of an oil (0.67 g).
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 7,233 (d, J=2,8 Hz, 1H); 7,018 (q, J=9 Hz, 1H); 6,877 (d, J= 8,6 Hz, 1H); 6,821 (dd, J=8,6, 2,9 Hz, 1H); 6,646 (ddd, J=11,7, 6,6, 3 Hz, 1H); 6,542 (dtd, J=9,1, 3,2, 1,7 Hz, 1H); 4,191 (q, J= 7,2 Hz, 2H); 1,150 (t, J= 7,1 Hz, 3H).1 H NMR (400 MHz) (CDCl 3) δ 7.233 (d, J = 2.8 Hz, 1H); 7.018 (q, J = 9 Hz, 1H); 6.877 (d, J = 8.6 Hz, 1H); 6.821 (dd, J = 8.6, 2.9 Hz, 1H); 6.646 (ddd, J = 11.7, 6.6, 3 Hz, 1H); 6.542 (dtd, J = 9.1, 3.2, 1.7 Hz, 1H); 4.191 (q, J = 7.2 Hz, 2H); 1,150 (t, J = 7.1 Hz, 3H).
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A la anilina producto del Ejemplo 28.2 (0,17 g) se le añadió cloruro de 2,4-diclorobencenosulfonilo ((0,15 g) en condiciones similares a las empleadas en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de cristales (80 mg) después de la cromatografía instantánea y la trituración con éter. pf 106-108ºC.To the aniline product of Example 28.2 (0.17 g) 2,4-dichlorobenzenesulfonyl chloride was added ((0.15 g) under conditions similar to those used in the Example 17.4. The title compound was obtained as crystals (80 mg) after instant chromatography and crushing with ether. mp 106-108 ° C.
RMN H^{1} (400 MHz)
(DMSO-d_{6}) \delta 10,974 (s, 1H); 8,030 (d,
J=8,5 Hz, 1H); 7,904 (d, J=1,9 Hz, 1H); 7,649 (dd,
J= 8,5, 2,1 Hz, 1H); 7,570 (d, J=2,7 Hz, 1H); 7,364
(d, J=9,2 Hz, 1H); 7,327 (dd, J=8,8, 2,7 Hz, 1H);
7,085 (d, J= 8,9 Hz,
1H); 6,981 (ddd, J= 9,7,
6,7, 3 Hz, 1H); 6,599 (dt, J=9, 1,4 Hz, 1H); 4,126 (q,
J= 7 Hz, 2H); 1,082 (t, J= 7 Hz, 3H).1 H NMR (400 MHz) (DMSO-d 6) δ 10.974 (s, 1H); 8.030 (d, J = 8.5 Hz, 1H); 7,904 (d, J = 1.9 Hz, 1H); 7.649 (dd, J = 8.5, 2.1 Hz, 1H); 7,570 (d, J = 2.7 Hz, 1H); 7.364 (d, J = 9.2 Hz, 1H); 7.327 (dd, J = 8.8, 2.7 Hz, 1H); 7.085 (d, J = 8.9 Hz,
1 HOUR); 6,981 (ddd, J = 9.7, 6.7, 3 Hz, 1H); 6.599 (dt, J = 9, 1.4 Hz, 1H); 4,126 (q, J = 7 Hz, 2H); 1,082 (t, J = 7 Hz, 3H).
C_{21} H_{15}NSO_{5}Cl_{2}F_{2} calc: %C 50,21 %H 3,01 %N 2,79 encontrado: %C 50,16 %H 3,03 %N 2,81.C 21 H 15 NSO 5 Cl 2 F 2 calc: % C 50.21% H 3.01% N 2.79 found:% C 50.16% H 3.03% N 2.81.
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Este ejemplo ilustra la preparación de 4-(3-cloro-5-piridiloxi)-5-(2,4-diclorobencenosulfonamido)tolueno.This example illustrates the preparation of 4- (3-Chloro-5-pyridyloxy) -5- (2,4-dichlorobenzenesulfonamido) toluene.
Se combinaron 2-fluoro-5-nitrotolueno (5,08 g) y 3-cloro-5-hidroxipiridina (4,25 g) a 80ºC utilizando un método similar al del Ejemplo 21.2 para proporcionar 7,1 g de 2-(3-cloro-5-piridiloxi)-5-nitrotolueno. pf 80-82ºC.They combined 2-fluoro-5-nitrotoluene (5.08 g) and 3-chloro-5-hydroxypyridine (4.25 g) at 80 ° C using a method similar to that of Example 21.2 to provide 7.1 g of 2- (3-Chloro-5-pyridyloxy) -5-nitrotoluene. mp 80-82 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,438 (d, J= 2 Hz, 1H); 8,316 (d, J=2,3 Hz, 1H); 8,210 (d, J= 2,6 Hz, 1H); 8,083 (d,d, J=8,8, 2,9 Hz, 1H); 7,337 (t, J= 2,2 Hz, 1H); 6,872 (t, J= 7,7 Hz, 1H); 6,913 (d, J= 8,8 Hz, 1H); 2,403 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.438 (d, J = 2 Hz, 1H); 8.316 (d, J = 2.3 Hz, 1H); 8.210 (d, J = 2.6 Hz, 1H); 8.083 (d, d, J = 8.8, 2.9 Hz, 1H); 7.337 (t, J = 2.2 Hz, 1H); 6.872 (t, J = 7.7 Hz, 1H); 6,913 (d, J = 8.8 Hz, 1H); 2.403 (s, 3 H).
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El derivado de nitrotolueno (2,96 g) producido en el Ejemplo 29.1 se convirtió en el derivado amínico correspondiente utilizando el método descrito en el Ejemplo 17.3 (con metanol/THF como disolvente). El compuesto del título se obtuvo en forma de un sólido (2,67 g). pf 48-50ºC.The nitrotoluene derivative (2.96 g) produced in Example 29.1 it became the amino derivative corresponding using the method described in Example 17.3 (with methanol / THF as solvent). The title compound is obtained as a solid (2.67 g). pf 48-50 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,629 (m, J= 2 Hz, 2H); 7,485 (t, J= 2,2 Hz, 1H); 7,220 (d, J= 8,4 Hz, 1H); 7,027 (d, J= 2,9 Hz, 1H); 6,971 (dd, J=8,4, 2,6 Hz, 1H); 2,512 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.629 (m, J = 2 Hz, 2H); 7.485 (t, J = 2.2 Hz, 1H); 7.220 (d, J = 8.4 Hz, 1H); 7.027 (d, J = 2.9 Hz, 1H); 6,971 (dd, J = 8.4, 2.6 Hz, 1H); 2,512 (s, 3H).
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Al aminotolueno producto del Ejemplo 29.2 (0,42 g) se le añadió cloruro de 2,4-diclorobencenosulfonilo (0,444 g) en condiciones similares a las empleadas en el Ejemplo 17,4. El compuesto del título se obtuvo en forma de un producto cristalino (0,473 g) después de la cromatografía instantánea y la trituración con hexano. pf 126-128ºC.To the aminotoluene product of Example 29.2 (0.42 g) chloride of 2,4-dichlorobenzenesulfonyl (0.444 g) in conditions similar to those used in Example 17.4. He title compound was obtained in the form of a crystalline product (0.473 g) after flash chromatography and crushing with hexane. mp 126-128 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,284 (s, 1H); 8,145 (s, 1H); 7,951 (d, J= 8,5 Hz, 1H); 7,557 (d, J= 2 Hz, 1H); 7,358 (dd, J= 8,5, 2 Hz, 1H); 7,127 (br s, 1H); 7,078 (m, 2H); 6,968 (dd, J=8,7, 2,6 Hz, 1H); 6,805 (d, J=8,7 Hz, 1H); 2,148 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.284 (s, 1H); 8.145 (s, 1 H); 7,951 (d, J = 8.5 Hz, 1H); 7.557 (d, J = 2 Hz, 1H); 7.358 (dd, J = 8.5, 2 Hz, 1H); 7,127 (br s, 1 H); 7.078 (m, 2H); 6,968 (dd, J = 8.7, 2.6 Hz, 1H); 6.805 (d, J = 8.7 Hz, 1H); 2,148 (s, 3 H).
C_{18}H_{13}N_{2}Cl_{3}SO_{3} calc: %C 48,72 %H 2,95 %N 6,31 encontrado: %C 48,81 %H 3,03 %N 6,25.C 18 H 13 N 2 Cl 3 SO 3 calc:% C 48.72% H 2.95% N 6.31 found:% C 48.81% H 3.03% N 6.25.
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 1-(3-cloro-5-piridiloxi)-4-(2,4-diclorobencenosulfonamido)benceno.This example (not of the claimed invention) illustrates the preparation of 1- (3-Chloro-5-pyridyloxy) -4- (2,4-dichlorobenzenesulfonamido) benzene.
Se combinaron 4-Fluoro-nitrobenceno (5,0 g) y 3-cloro-5-hidroxipiridina (4,59 g) a 60ºC utilizando un método similar al del Ejemplo 21.2 para proporcionar 7,78 g de 4-(3-cloro-5-piridiloxi)nitrobenceno. pf 80-82ºC.They combined 4-Fluoro-nitrobenzene (5.0 g) and 3-chloro-5-hydroxypyridine (4.59 g) at 60 ° C using a method similar to that of Example 21.2 to provide 7.78 g of 4- (3-Chloro-5-pyridyloxy) nitrobenzene. mp 80-82 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,492 (d, J= 1,9 Hz, 1H); 8,380 (d, J= 2,4 Hz, 1H); 8,289 (d, J= 9,2 Hz, 2H); 7,443 (d, J=2,2 Hz, 1H); 7,115 (d, J=9,2 Hz, 1H).1 H NMR (400 MHz) (CDCl 3) δ 8.492 (d, J = 1.9 Hz, 1H); 8.380 (d, J = 2.4 Hz, 1H); 8.289 (d, J = 9.2 Hz, 2H); 7.443 (d, J = 2.2 Hz, 1H); 7.115 (d, J = 9.2 Hz, 1H).
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El derivado de nitrobenceno (7,7 g) producido en el Ejemplo 30.1 se convirtió en el derivado de anilina correspondiente utilizando el método descrito en el Ejemplo 17.3 (con metanol/THF como disolvente). El compuesto del título se obtuvo en forma de un sólido (6,7 g).The nitrobenzene derivative (7.7 g) produced in Example 30.1 became the aniline derivative corresponding using the method described in Example 17.3 (with methanol / THF as solvent). The title compound is obtained in the form of a solid (6.7 g).
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A la anilina producto del Ejemplo 30.2 (0,45 g) se le añadió cloruro de 2,4-diclorobenceno sulfonilo (0,533 g) en condiciones similares a las empleadas en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino (0,643 g) después de la cromatografía instantánea y la trituración con acetato de etilo/hexano. pf 132-134ºC.To the aniline product of Example 30.2 (0.45 g) 2,4-dichlorobenzene sulfonyl chloride was added (0.533 g) under conditions similar to those used in the Example 17.4. The title compound was obtained in the form of a product. crystalline (0.643 g) after flash chromatography and the trituration with ethyl acetate / hexane. pf 132-134 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,709 (s, 1H); 8,388 (d, J= 1,8 Hz, 1H); 8,251 (d, J= 2 Hz, 1H); 7,987 (d, J= 8,5 Hz, 1H); 7,874 (d, J= 2 Hz, 1H); 7,610 (dd, J= 8,7, 2 Hz, 1H); 7485 (d, J= 2,1 Hz, 1H); 7,133 (d, J=9 Hz, 2H); 7,039 (d, J= 9 Hz, 2H).1 H NMR (400 MHz) (CDCl 3) δ 10.709 (s, 1H); 8.388 (d, J = 1.8 Hz, 1H); 8.251 (d, J = 2 Hz, 1H); 7,987 (d, J = 8.5 Hz, 1H); 7.874 (d, J = 2 Hz, 1H); 7.610 (dd, J = 8.7, 2 Hz, 1H); 7485 (d, J = 2.1 Hz, 1H); 7.133 (d, J = 9 Hz, 2H); 7.039 (d, J = 9 Hz, 2H).
C_{17}H_{11}N_{2}Cl_{3}SO_{3} calc: %C 47,52 %H 2,58 %N 6,52 encontrado: %C 47,69 %H 2,65 %N 6,51.C 17 H 11 N 2 Cl 3 SO 3 calc:% C 47.52% H 2.58% N 6.52 found:% C 47.69% H 2.65% N 6.51.
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Este ejemplo ilustra la preparación de 2-(3-cloro-5-piridiloxi)-5-(5-trifluorometil-2-piridinosulfonamido)tolueno.This example illustrates the preparation of 2- (3-Chloro-5-pyridyloxy) -5- (5-trifluoromethyl-2-pyridinosulfonamido) toluene.
La anilina producida en el Ejemplo 29.2 (0,195 g) se convirtió en el compuesto del título utilizando el cloruro de sulfonilo producido en el Ejemplo 21.5 (1,5 mL de solución), de una manera similar a la descrita en el Ejemplo 21.6. El compuesto del título se obtuvo en forma de un producto cristalino (85 mg) después de la filtración del producto bruto a través de sílice y la trituración en éter. pf 147-148ºC.The aniline produced in Example 29.2 (0.195 g) became the title compound using the chloride of sulfonyl produced in Example 21.5 (1.5 mL of solution), of a similar to that described in Example 21.6. The compound of title was obtained in the form of a crystalline product (85 mg) after of the filtration of the crude product through silica and the ether crushing. mp 147-148 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,795 (s, 1H); 9,192 (br s, 1H); 8,509 (dd, J= 8,2, 1,9 Hz, 1H); 8,352 (d, J= 1,9 Hz, 1H); 8,190 (d, J= 2,6 Hz, 1H); 8,171 (d, J= 8,6 Hz, 1H); 7,334 (t, J= 2,2 Hz, 1H); 7,128 (d, J= 2,2 Hz, 1H); 7,017 (dd, J=8,6, 2,8 Hz, 1H); 6,936 (d, J= 8,6 Hz, 1H); 2,082 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 10.795 (s, 1H); 9,192 (br s, 1 H); 8.509 (dd, J = 8.2, 1.9 Hz, 1H); 8.352 (d, J = 1.9 Hz, 1H); 8.190 (d, J = 2.6 Hz, 1H); 8.171 (d, J = 8.6 Hz, 1H); 7.334 (t, J = 2.2 Hz, 1H); 7.128 (d, J = 2.2 Hz, 1H); 7.017 (dd, J = 8.6, 2.8 Hz, 1H); 6,936 (d, J = 8.6 Hz, 1H); 2,082 (s, 3 H).
C_{18}H_{13}N_{3}Cl_{3}SO_{3}\cdot0,25H_{2}O calc: %C 48,22 %H 3,04 %N 9,37 encontrado: %C 48,16 %H 2,97 %N 9,22.C_18 H_ {13} N_ {3} Cl_ {3} SO_ {3} \ cdot0.25H2 O calc:% C 48.22% H 3.04% N 9.37 found:% C 48.16% H 2.97% N 9.22.
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 1-(3-cloro-5-piridiloxi)-2-(2,4-diclorobencenosulfonamido)benceno.This example (not of the claimed invention) illustrates the preparation of 1- (3-Chloro-5-pyridyloxy) -2- (2,4-dichlorobenzenesulfonamido) benzene.
Se combinaron 2-fluoro-nitrobenceno (5,0 g) y 3-cloro-5-hidroxipiridina (4,59 g) a 80ºC durante 1 hr, utilizando un método similar al del Ejemplo 21.2 para proporcionar 8,56 g de 2-(3-cloro-5-piridiloxi)nitrobenceno.They combined 2-fluoro-nitrobenzene (5.0 g) and 3-chloro-5-hydroxypyridine (4.59 g) at 80 ° C for 1 hr, using a method similar to that of Example 21.2 to provide 8.56 g of 2- (3-Chloro-5-pyridyloxy) nitrobenzene.
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El derivado de nitrobenceno (8,56 g) producido en 32.1 se convirtió en el derivado de anilina correspondiente utilizando el método descrito en el Ejemplo 17.3. El compuesto del título se obtuvo en forma de un sólido (4,96 g). pf 90-92ºC.The nitrobenzene derivative (8.56 g) produced in 32.1 it became the corresponding aniline derivative using the method described in Example 17.3. The compound of Title was obtained as a solid (4.96 g). pf 90-92 ° C.
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A la anilina producto del Ejemplo 32,2 (0,41 g) se le añadió cloruro de 2,4-diclorobencenosulfonilo (0,452 g) en condiciones similares a las empleadas en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino (0,278 g) después de la cromatografía instantánea y la trituración con cloruro de metileno/metanol. pf 168-170ºC.To the aniline product of Example 32.2 (0.41 g) 2,4-dichlorobenzenesulfonyl chloride was added (0.452 g) under conditions similar to those used in the Example 17.4. The title compound was obtained in the form of a product. crystalline (0.278 g) after flash chromatography and the trituration with methylene chloride / methanol. pf 168-170 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,373 (s, 1H); 8,318 (d, J= 1,9 Hz, 1H); 7,982 (d, J= 2,2 Hz, 1H); 7,793 (d, J= 8,6 Hz, 1H); 7,538 (d, J= 2,2 Hz, 1H); 7,474 (dd, J= 8,4, 2 Hz, 1H); 7,429 (dd, J= 7,6, 2 Hz, 1H); 7,264 (m, 2H); 7,070 (dd, J=7,6, 2 Hz, 1H); 6,897 (t, J= 2,2 Hz, 1H).1 H NMR (400 MHz) (CDCl 3) δ 10.373 (s, 1H); 8.318 (d, J = 1.9 Hz, 1H); 7,982 (d, J = 2.2 Hz, 1H); 7.793 (d, J = 8.6 Hz, 1H); 7.538 (d, J = 2.2 Hz, 1H); 7.474 (dd, J = 8.4, 2 Hz, 1H); 7.429 (dd, J = 7.6, 2 Hz, 1H); 7.264 (m, 2H); 7.070 (dd, J = 7.6, 2 Hz, 1H); 6.897 (t, J = 2.2 Hz, 1H).
C_{17}H_{11}N_{2}Cl_{3}SO_{3} calc: %C 47,52 %H 2,58 %N 6,52 encontrado: %C 47,26 %H 2,57 %N 6,42.C 17 H 11 N 2 Cl 3 SO 3 calc:% C 47.52% H 2.58% N 6.52 found:% C 47.26% H 2.57% N 6.42.
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 1-(3-cloro-5-piridiloxi)-2-(4-metoxibencenosulfonamido)benceno.This example (not of the claimed invention) illustrates the preparation of 1- (3-Chloro-5-pyridyloxy) -2- (4-methoxybenzenesulfonamido) benzene.
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La anilina producida en el Ejemplo 32,2 (0,41 g) se convirtió en el compuesto del título utilizando cloruro de 4-metoxibencenosulfonilo (0,384 g), de una manera similar a la descrita en el Ejemplo 17.4. El compuesto del título se obtuvo en forma de un producto cristalino (0,28 g) después de la cromatografía instantánea y la trituración con éter. pf 128,5-131ºC.The aniline produced in Example 32.2 (0.41 g) became the title compound using chloride 4-methoxybenzenesulfonyl (0.384 g), in one way similar to that described in Example 17.4. The title compound it was obtained in the form of a crystalline product (0.28 g) after flash chromatography and ether trituration. pf 128.5-131 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 9,905 (s, 1H); 8,311 (d, J= 1,8 Hz, 1H); 8,033 (d, J= 2,6 Hz, 1H); 7,561 (d, J= 8,9 Hz, 2H); 7,456 (dd, J= 7,6, 3 Hz, 1H); 7,20 (m, 2H); 7,026 (dd, J= 7,4, 3 Hz, 1H); 6,908 (d, J= 8,9 Hz, 1H); 6,897 (d, J=3 Hz, 1H); 3,772 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 9.905 (s, 1H); 8.311 (d, J = 1.8 Hz, 1H); 8.033 (d, J = 2.6 Hz, 1H); 7.561 (d, J = 8.9 Hz, 2H); 7.456 (dd, J = 7.6, 3 Hz, 1H); 7.20 (m, 2 H); 7.026 (dd, J = 7.4, 3 Hz, 1H); 6,908 (d, J = 8.9 Hz, 1H); 6.897 (d, J = 3 Hz, 1H); 3,772 (s, 3 H).
C_{18}H_{15}N_{2}ClSO_{4} calc: %C 55,32 %H 3,87 %N 7,17 encontrado: %C 55,35 %H 3,82 %N 7,08.C 18 H 15 N 2 ClSO 4 calc:% C 55.32 % H 3.87% N 7.17 found:% C 55.35% H 3.82% N 7.08.
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 1-(3-cloro-5-piridiloxi)-2-(4-yodobencenosulfonamido)benceno.This example (not of the claimed invention) illustrates the preparation of 1- (3-Chloro-5-pyridyloxy) -2- (4-iodobenzenesulfonamido) benzene.
La anilina producida en el Ejemplo 32,2 (0,4 g) se convirtió en el compuesto del título utilizando cloruro de 4-yodobencenosulfonilo (0,557 g). El compuesto del título se obtuvo en forma de un producto cristalino (0,54 g). pf 168-170ºC.The aniline produced in Example 32.2 (0.4 g) became the title compound using chloride 4-iodobenzenesulfonyl (0.557 g). The compound of Title was obtained in the form of a crystalline product (0.54 g). pf 168-170 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 10,170 (s, 1H); 8,332 (d, J= 3,1 Hz, 1H); 8,021 (d, J= 2,6 Hz, 1H); 7,789 (d, J= 7,9 Hz, 2H); 7,42 (m, 1H); 7,394 (d, J= 7,9 Hz, 2H); 7,229 (m, 2H); 7,042 (m, 1H); 6,942 (t, J= 1,9 Hz, 1H).1 H NMR (400 MHz) (CDCl 3) δ 10,170 (s, 1H); 8.332 (d, J = 3.1 Hz, 1H); 8.021 (d, J = 2.6 Hz, 1H); 7.789 (d, J = 7.9 Hz, 2H); 7.42 (m, 1 H); 7.394 (d, J = 7.9 Hz, 2H); 7.229 (m, 2H); 7.042 (m, 1 H); 6,942 (t, J = 1.9 Hz, 1H).
C_{17}H_{12}N_{2}CUSO_{3} calc: %C 41,95 %H 2,49 %N 5,76 encontrado: %C 42,00 %H 2,46 %N 5,73.C 17 H 12 N 2 CUSO 3 calc:% C 41.95 % H 2.49% N 5.76 found:% C 42.00% H 2.46% N 5.73.
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Este ejemplo ilustra la preparación de N-(2-furanilmetil) 5-(2,4-dicloro-5-metilbencenosulfonamido)-2-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of N- (2-furanylmethyl) 5- (2,4-Dichloro-5-methylbenzenesulfonamido) -2- (3-chloro-5-pyridyloxy) benzamide.
A una solución 0,2 M de ácido 2-fluoro-5-nitrobenzoico (1,0 g, 5,4 mmoles, Aldrich) en THF anhidro a temperatura ambiente se le añadieron furfurilamina (1,1 g, 5,9 mmoles), HBTU (2,24 g, 5,9 mmoles, Chem-Impex), HOBT (0,8 g, 5,9 mmoles, Novabiochem) y NMM (0,59 mL, 5,4 mmoles, Aldrich). La solución resultante se agitó durante 18 hr. A la mezcla de reacción se le añadió una solución 1 M de ácido clorhídrico acuoso (30 mL). La mezcla bruta se extrajo 3x con EtOAc (50 mL). Las capas orgánicas se combinaron, se lavaron una vez con una solución acuosa saturada de NaHCO_{3} (100 mL), una vez con salmuera (100 mL), se secaron sobre Na_{2}SO_{4}, y se concentraron a vacío para producir 1,4 g (100%) de producto en forma de un sólido de color blanquecino que se utilizó sin purificación adicional.To a 0.2 M acid solution 2-fluoro-5-nitrobenzoic (1.0 g, 5.4 mmol, Aldrich) in anhydrous THF at room temperature furfurylamine (1.1 g, 5.9 mmol), HBTU (2.24 g, 5.9 were added mmol, Chem-Impex), HOBT (0.8 g, 5.9 mmol, Novabiochem) and NMM (0.59 mL, 5.4 mmol, Aldrich). The solution resulting was stirred for 18 hr. The reaction mixture is given added a 1M solution of aqueous hydrochloric acid (30 mL). The Crude mixture was extracted 3x with EtOAc (50 mL). Organic layers they were combined, washed once with a saturated aqueous solution NaHCO3 (100 mL), once with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to yield 1.4 g (100%) of product in the form of an off-white solid that It was used without further purification.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 9,11 (t, J = 5,6Hz, 1H), 8,45-8,35 (m, 2H), 7,67-7,55 (m, 2H), 6,41 (dd, J = 3,28, 1,76 Hz, 1H), 6,37 (d, J = 2,8 Hz, 1H), 4,5 (d, J = 5,8 Hz, 2H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 9.11 (t, J = 5.6Hz, 1H), 8.45-8.35 (m, 2H), 7.67-7.55 (m, 2H), 6.41 (dd, J = 3.28, 1.76 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 4.5 (d, J = 5.8 Hz, 2H).
MS (IE): m/z 264 (15, M+), 263 (100, M-H).MS (IE): m / z 264 (15, M +), 263 (100, M-H).
Anal. Calcd para C_{12}H_{9}FN_{2}O_{4}: C, 54,55; H, 3,43; N, 10,6. Encontrado: C, 54,74; H, 3,54; N, 10,47.Anal. Calcd for C 12 H 9 FN 2 O 4: C, 54.55; H, 3.43; N, 10.6. Found: C, 54.74; H, 3.54; N, 10.47.
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A una solución 0,08 M de N-(2-furanilmetil)-2-fluoro-5-nitrobenzamida (2,64 g, 10 mmoles, del Ejemplo 35,1) en DMSO anhidro se le añadió 5-cloro-3-piridinol (1,36 g, 10,5 mmoles, Acros) seguido de K_{2}CO_{3} (1,38 g, 10 mmoles). La mezcla resultante se agitó a temperatura ambiente durante 1 hr. La mezcla de reacción bruta se diluyó con una solución 1 M de ácido clorhídrico acuoso (125 mL) y se extrajo 3x con EtOAc (125 mL). Las capas orgánicas se combinaron y se lavaron dos veces con salmuera (200 mL), se secaron sobre Na_{2}SO_{4}, y se concentraron a vacío para producir 3,7 g (100%) de N-(2-furanilmetil) 5-nitro-2-(3-cloro-5-piridiloxi)benzamida en forma de una espuma de color amarillo descolorido que se utilizó sin purificación adicional.At a 0.08 M solution of N- (2-furanylmethyl) -2-fluoro-5-nitrobenzamide (2.64 g, 10 mmol, from Example 35.1) in anhydrous DMSO was added 5-chloro-3-pyridinol (1.36 g, 10.5 mmol, Acros) followed by K 2 CO 3 (1.38 g, 10 mmoles). The resulting mixture was stirred at room temperature for 1 hr. The crude reaction mixture was diluted with a 1 M solution of aqueous hydrochloric acid (125 mL) and 3x was extracted with EtOAc (125 mL). The organic layers were combined and washed twice with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to yield 3.7 g (100%) of N- (2-furanylmethyl) 5-nitro-2- (3-chloro-5-pyridyloxy) benzamide in the form of a colorless yellow foam that was used Without further purification.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 9,04 (t, J = 5,6Hz, 1H), 8,56 (d, J = 1,83 Hz, 1H), 8,48 (d, J = 2,2 Hz, 1H), 8,45 (d, J = 2,8 Hz, 1H), 8,31 (dd, J = 9,2, 2,9 Hz, 1H), 7,88 (dd, J = 2,4, 2,2 Hz, 1H), 7,55 (d, J = 1,8 Hz, 1H), 7,23 (d, J = 9,1 Hz, 1H), 6,38 (dd, J = 3,1, 1,9 Hz, 1H), 6,25 (d, J = 3,2 Hz, 1H), 4,6 (d, J = 5,6 Hz, 2H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 9.04 (t, J = 5.6Hz, 1H), 8.56 (d, J = 1.83 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.31 (dd, J = 9.2, 2.9 Hz, 1H), 7.88 (dd, J = 2.4, 2.2 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 9.1 Hz, 1H), 6.38 (dd, J = 3.1, 1.9 Hz, 1H), 6.25 (d, J = 3.2 Hz, 1H), 4.6 (d, J = 5.6 Hz, 2H).
MS (IE): m/z 375 (7, M-H), 374 (38, M-H), 373 (22, M-H), 372 (100, M-H).MS (IE): m / z 375 (7, MH), 374 (38, MH), 373 (22, MH), 372 (100, MH).
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A una solución 0,08 M de N-(2-furanilmetil)-5-nitro-2-(3-cloro-5-piridiloxi)benzamida (3,7 g, 10 mmoles, preparada en el Ejemplo 35.2) en MeOH se le añadió una suspensión acuosa al 50% de níquel Raney (\sim6 mL). Después se hizo burbujear hidrógeno a través de la solución resultante durante un minuto. La mezcla resultante se agitó a temperatura ambiente en atmósfera de hidrógeno durante 16 hr. La mezcla de reacción bruta se filtró a través de un lecho de Celite® y la torta del filtro se lavó 3x con MeOH. OBSÉRVESE: el níquel Raney es pirofórico y siempre se debe mantener mojado con disolvente durante la filtración. El níquel Raney se puede sofocar añadiendo HCl acuoso 6 M. El producto filtrado se concentró en presencia de benceno para eliminar azeotrópicamente el agua. El residuo se purificó mediante cromatografía (MeOH al 1-3% en CH_{2}Cl_{2}) para producir 2,6 g (76%) de N-(2-furanilmetil)-5-amino-2-(3-cloro-5-piridiloxi)benzamida en forma de un sólido de color pardo claro.At a 0.08 M solution of N- (2-furanylmethyl) -5-nitro-2- (3-chloro-5-pyridyloxy) benzamide (3.7 g, 10 mmol, prepared in Example 35.2) in MeOH is given added a 50% aqueous suspension of Raney nickel (~ 6 mL). Then hydrogen was bubbled through the solution resulting for one minute. The resulting mixture was stirred at room temperature in hydrogen atmosphere for 16 hr. The crude reaction mixture was filtered through a bed of Celite® and the filter cake was washed 3x with MeOH. NOTE: nickel Raney is pyrophoric and should always be kept wet with solvent during filtration. Raney nickel can suffocate adding 6M aqueous HCl. The filtrate was concentrated in presence of benzene to azeotropically remove water. He residue was purified by chromatography (MeOH at 1-3% in CH2Cl2) to produce 2.6 g (76%) from N- (2-furanylmethyl) -5-amino-2- (3-chloro-5-pyridyloxy) benzamide in the form of a light brown solid.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,65 (t, J = 5,9Hz, 1H), 8,28 (d, J = 2,2 Hz, 1H), 8,14 (d, J = 2,6 Hz, 1H), 7,48 (d, J = 1,8 Hz, 1H), 7,22 (dd, J = 2,4, 2,0 Hz, 1H), 6,89 (d, J = 8,7 Hz, 1H), 6,78 (d, J = 2,8 Hz, 1H), 6,69 (dd, J = 8,6, 2,7 Hz, 1H), 6,31 (dd, J = 3,2, 1,6 Hz, 1H), 6,05 (d, J = 3,3 Hz, 1H), 5,33 (s, 2H) 4,29 (d, J = 5,9 Hz, 2H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 8.65 (t, J = 5.9Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 2.4, 2.0 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.8 Hz, 1H), 6.69 (dd, J = 8.6, 2.7 Hz, 1H), 6.31 (dd, J = 3.2, 1.6 Hz, 1H), 6.05 (d, J = 3.3 Hz, 1H), 5.33 (s, 2H) 4.29 (d, J = 5.9 Hz, 2H).
MS (IE): m/z 347 (11, M+H), 346 (32, M+H), 345 (20, M+H), 344 (100, M+H).MS (IE): m / z 347 (11, M + H), 346 (32, M + H), 345 (20, M + H), 344 (100, M + H).
Anal. Calcd para C_{17}H_{14}ClN_{3}O_{3}: C, 59,4; H, 4,1; N, 12,22; Cl, 10,31. Encontrado: C, 59,45; H, 4,17; N, 12,08; Cl, 10,43.Anal. Calcd for C 17 H 14 ClN 3 O 3: C, 59.4; H, 4.1; N, 12.22; Cl, 10.31. Found: C, 59.45; H, 4.17; N, 12.08; Cl, 10.43.
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A una solución 0,2 M de N-(2-furanilmetil)-5-amino-2-(3-cloro-5-piridiloxi)benzamida (2,6 g, 7,6 mmoles, preparada en el Ejemplo 35,3) en una solución de THF/CH_{2}Cl_{2} 1:1 se le añadió piridina (0,67 mL, 8,3 mmoles) seguido de cloruro de 2,4-dicloro-5-metilbenceno sulfonilo (2,16 g, 8,3 mmoles). La mezcla resultante se agitó durante 21 hr. Se añadió una solución acuosa 1 M de HCl (100 mL) y la mezcla de reacción bruta se extrajo 3x con EtOAc (100 mL). Las capas orgánicas se combinaron y se lavaron una vez con una solución de salmuera (200 mL), se secaron sobre Na_{2}SO_{4}, y se concentraron a vacío. El sólido bruto se purificó mediante cromatografía (EtOAc al 10-40% en hexano) para producir 3,86 g (90%) de producto en forma de un sólido de color blanquecino.To a 0.2 M solution of N- (2-furanylmethyl) -5-amino-2- (3-chloro-5-pyridyloxy) benzamide (2.6 g, 7.6 mmol, prepared in Example 35.3) in a solution of THF / CH 2 Cl 2 1: 1 was added pyridine (0.67 mL, 8.3 mmoles) followed by chloride 2,4-dichloro-5-methylbenzene sulfonyl (2.16 g, 8.3 mmol). The resulting mixture was stirred. for 21 hr. A 1 M aqueous solution of HCl (100 mL) was added and The crude reaction mixture was extracted 3x with EtOAc (100 mL). The Organic layers were combined and washed once with a solution brine (200 mL), dried over Na2SO4, and dried concentrated in vacuo. The crude solid was purified by chromatography (10-40% EtOAc in hexane) to produce 3.86 g (90%) of product in the form of a colored solid whitish
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Este ejemplo ilustra la preparación de N-etil-3-(2,4-dicloro-5-metilbencenosulfonamido)-4-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation of N-ethyl-3- (2,4-dichloro-5-methylbenzenesulfonamido) -4- (3-chloro-5-pyridyloxy) benzamide.
La N-etil-4-fluoro-3-nitrobenzamida se sintetizó (100%) de una manera similar a la descrita en el Ejemplo 35.1, sustituyendo una solución 2 M de etilamina en THF por furfurilamina.The N-ethyl-4-fluoro-3-nitrobenzamide it was synthesized (100%) in a manner similar to that described in the Example 35.1, substituting a 2M solution of ethylamine in THF for furfurylamine
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,82 (t, J = 4,4 Hz, 1H), 8,62 (dd, J = 7,3, 2,4 Hz, 1H), 8,26 (ddd, J = 8,3, 6,7, 2,4 Hz, 1H), 7,7 (dd, J =11,1, 8,8 Hz, 1H), 3,3 (pentete, J = 7,2 Hz, 2H), 1,15 (t, J = 7,3 Hz, 3H).1 H NMR (400 MHz, DMSO-d 6) δ 8.82 (t, J = 4.4 Hz, 1H), 8.62 (dd, J = 7.3, 2.4 Hz, 1H), 8.26 (ddd, J = 8.3, 6.7, 2.4 Hz, 1H), 7.7 (dd, J = 11.1, 8.8 Hz, 1H), 3.3 (whit, J = 7.2 Hz, 2H), 1.15 (t, J = 7.3 Hz, 3H).
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La N-etil-3-nitro-4-(3-cloro-5-piridiloxi)benzamida se sintetizó (100%) de una manera similar a la descrita en el Ejemplo 35.2, comenzando con N-etil-4-fluoro-3-nitrobenzamida.The N-ethyl-3-nitro-4- (3-chloro-5-pyridyloxy) benzamide it was synthesized (100%) in a manner similar to that described in the Example 35.2, starting with N-ethyl-4-fluoro-3-nitrobenzamide.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,78 (t, J = 5,3 Hz, 1H), 8,59 (d, J = 2,2 Hz, 1H), 8,53 (d, J = 2,1 Hz, 1H), 8,48 (d, J = 2,3 Hz, 1H), 8,18 (dd, J = 8,7, 2,2 Hz, 1H), 7,89 (dd, J = 2,2, 2,2 Hz, 1H), 7,42 (d, J = 8,6 Hz, 1H), 3,4-3,2 (m, 2H), 1,14 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d_6) δ 8.78 (t, J = 5.3 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.7, 2.2 Hz, 1H), 7.89 (dd, J = 2.2, 2.2 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 3.4-3.2 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 325 (8, M+H), 324 (40, M+H), 323 (20, M+H), 322 (100, M+H).MS (IE): m / z 325 (8, M + H), 324 (40, M + H), 323 (20, M + H), 322 (100, M + H).
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La N-etil-3-amino-4-(3-cloro-5-piridiloxi)benzamida se sintetizó (100%) de una manera similar a la descrita en el Ejemplo 35.3, comenzando con el producto del Ejemplo 36.2.The N-ethyl-3-amino-4- (3-chloro-5-pyridyloxy) benzamide it was synthesized (100%) in a manner similar to that described in the Example 35.3, starting with the product of Example 36.2.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,34 (d, J = 2,1 Hz, 1H), 8,28 (t, J = 6,4 Hz, 1H), 8,25 (d, J = 2,3 Hz, 1H), 7,31 (dd, J = 2,5, 2,3 Hz, 1H), 7,03 (dd, J = 8,4, 2,1 Hz, 1H), 6,96 (d, J = 8,3 Hz, 1H), 5,3 (s, 2H), 3,3 (pentete, J = 7,1 Hz, 2H), 1,15 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d 6) δ 8.34 (d, J = 2.1 Hz, 1H), 8.28 (t, J = 6.4 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 2.5, 2.3 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.3 (s, 2H), 3.3 (Pentete, J = 7.1 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 294 (8, M+H), 292 (23, M+H).MS (IE): m / z 294 (8, M + H), 292 (23, M + H).
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La N-etil-3-(2,4-dicloro-5-metilbencenosulfonamido)-4-(3-cloro-5-piridiloxi)benzamida se sintetizó (71%) de una manera similar a la descrita en el Ejemplo 35.4, comenzando con el producto del Ejemplo 36.3.The N-ethyl-3- (2,4-dichloro-5-methylbenzenesulfonamido) -4- (3-chloro-5-pyridyloxy) benzamide it was synthesized (71%) in a manner similar to that described in the Example 35.4, starting with the product of Example 36.3.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 10,4 (s, 1H), 8,55 (t, J = 5,6 Hz, 1H), 8,34 (d, J = 2,0 Hz, 1H), 7,99 (d, J = 2,5 Hz, 1H), 7,96 (d, J = 2,2 Hz, 1H), 7,75 (dd, J = 8,5, 2,2 Hz, 1H), 7,74 (s, 1H), 7,44 (s, 1H), 7,12 (d, J = 8,6 Hz, 1H), 6,95 (dd, J = 2,4, 2,2 Hz, 1H), 3,28 (pentete, J = 7,2 Hz, 2H), 2,24 (s, 3H), 1,12 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 10.4 (s, 1H), 8.55 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 8.5, 2.2 Hz, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.95 (dd, J = 2.4, 2.2 Hz, 1H), 3.28 (whit, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 520 (6, M+H), 519 (10, M+H), 518 (40, M+H), 517 (26, M+H), 516 (100, M+H), 515 (25, M+H), 514 (100, M+H).MS (IE): m / z 520 (6, M + H), 519 (10, M + H), 518 (40, M + H), 517 (26, M + H), 516 (100, M + H), 515 (25, M + H), 514 (100, M + H).
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Este ejemplo ilustra la preparación N-etil-2-(2,4-dicloro-5-metilbencenosulfonamido)-5-(3-cloro-5-piridiloxi)benzamida.This example illustrates the preparation N-ethyl-2- (2,4-dichloro-5-methylbenzenesulfonamido) -5- (3-chloro-5-pyridyloxy) benzamide.
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La N-etil-5-fluoro-2-nitrobenzamida se sintetizó (100%) de una manera similar a los métodos descritos en el Ejemplo 35.1The N-ethyl-5-fluoro-2-nitrobenzamide it was synthesized (100%) in a manner similar to the methods described in Example 35.1
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,65 (t, J = 4,9 Hz, 1H), 8,16 (dd, J = 8,8, 4,8 Hz, 1H), 7,57-7,47 (m, 2H), 3,24 (pentete, J = 7,2 Hz, 2H), 1,11 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d 6) δ 8.65 (t, J = 4.9 Hz, 1H), 8.16 (dd, J = 8.8, 4.8 Hz, 1H), 7.57-7.47 (m, 2H), 3.24 (whit, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 211 (40, M-H).MS (IE): m / z 211 (40, MH).
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La N-etil-2-nitro-5-(3-cloro-5-piridiloxi)benzamida se sintetizó (100%) de una manera similar a los métodos descritos en el Ejemplo 35.2.The N-ethyl-2-nitro-5- (3-chloro-5-pyridyloxy) benzamide it was synthesized (100%) in a manner similar to the methods described in Example 35.2.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,62 (t, J = 5,4 Hz, 1H), 8,58 (d, J = 1,9 Hz, 1H), 8,49 (d, J = 2,2 Hz, 1H), 8,12 (d, J = 9 Hz, 1H), 7,94 (dd, J = 2,4, 2,1 Hz, 1H), 7,3 (dd, J = 8,9, 2,7 Hz, 1H), 7,24 (d, J = 2,7 Hz, 1H), 3,22 (pentete, J = 7,0 Hz, 2H), 1,1 (t, J = 7,3 Hz, 3H).1 H NMR (400 MHz, DMSO-d 6) δ 8.62 (t, J = 5.4 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.49 (d, J = 2.2 Hz, 1H), 8.12 (d, J = 9 Hz, 1H), 7.94 (dd, J = 2.4, 2.1 Hz, 1H), 7.3 (dd, J = 8.9, 2.7 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 3.22 (whit, J = 7.0 Hz, 2H), 1.1 (t, J = 7.3 Hz, 3H).
MS (IE): m/z 322 (8, M-H), 320 (20, M-H), 251 (30, M-CONHEt), 249 (100, M-CONHEt).MS (IE): m / z 322 (8, M-H), 320 (20, M-H), 251 (30, M-CONHEt), 249 (100, M-CONHEt).
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La N-etil-2-amino-5-(3-cloro-5-piridiloxi)benzamida se sintetizó (88%) de una manera similar a los métodos descritos en el Ejemplo 35.3.The N-ethyl-2-amino-5- (3-chloro-5-pyridyloxy) benzamide it was synthesized (88%) in a similar way to the methods described in Example 35.3.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,32 (d, J = 2,0 Hz, 1H), 8,27 (d, J = 2,4 Hz, 1H), 8,23 (t, J = 5,5 Hz, 1H) 7,36 (dd, J = 2,4, 2,0 Hz, 1H), 7,03 (dd, J = 8,9, 2,7 Hz, 1H), 6,77 (d, J = 8,9 Hz, 1H), 6,46 (s, 2H), 3,6-3,18 (m, 2H), 1,08 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d 6) δ 8.32 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.23 (t, J = 5.5 Hz, 1H) 7.36 (dd, J = 2.4, 2.0 Hz, 1H), 7.03 (dd, J = 8.9, 2.7 Hz, 1H), 6.77 (d, J = 8.9 Hz, 1H), 6.46 (s, 2H), 3.6-3.18 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 292 (30, M-H), 290 (100, M-H).MS (IE): m / z 292 (30, MH), 290 (100, MH).
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La N-etil-2-(2,4-dicloro-5-metilbencenosulfonamido)-5-(3-cloro-5-piridiloxi)benzamida se sintetizó (35%) utilizando métodos similares a los descritos en el Ejemplo 35.4.The N-ethyl-2- (2,4-dichloro-5-methylbenzenesulfonamido) -5- (3-chloro-5-pyridyloxy) benzamide it was synthesized (35%) using methods similar to those described in Example 35.4.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 12,0 (s, 1H), 8,85 (t, J = 4,9 Hz, 1H), 8,42 (d, J = 1,9 Hz, 1H), 8,31 (d, J = 2,6 Hz, 1H), 8,08 (d, J = 8,6 Hz, 1H), 7,89 (d, J = 2,0 Hz, 1H), 7,65 (dd, J = 8,6, 2,1 Hz, 1H), 7,58 (dd, J = 2,3, 2,2 Hz, 1H), 7,55 (d, J = 2,8 Hz, 1H), 7,43 (d, J = 9 Hz, 1H), 7,25 (dd, J = 9, 2,8 Hz, 1H), 3,25 (pentete, J = 7,2 Hz, 2H), 1,1 (t, J = 7,2 Hz, 3H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 12.0 (s, 1H), 8.85 (t, J = 4.9 Hz, 1H), 8.42 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 1H), 7.58 (dd, J = 2.3, 2.2 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 9 Hz, 1H), 7.25 (dd, J = 9, 2.8 Hz, 1H), 3.25 (whit, J = 7.2 Hz, 2H), 1.1 (t, J = 7.2 Hz, 3H).
MS (IE): m/z 503 (10, M-H), 502 (35, M-H), 501 (20, M-H), 500 (100, M-H), 499 (25, M-H), 498 (95, M-H).MS (IE): m / z 503 (10, M-H), 502 (35, M-H), 501 (20, M-H), 500 (100, M-H), 499 (25, M-H), 498 (95, M-H).
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Este ejemplo (no de la invención reivindicada) ilustra la preparación de 5-(3-(4-metoxibenceno-sulfonamido)fenoxi))-3-cloropiridina y 5-(3-(2,4-diclorobencenosulfonamido)fenoxi))-3-cloropiridina.This example (not of the claimed invention) illustrates the preparation of 5- (3- (4-methoxybenzene sulfonamido) phenoxy)) - 3-chloropyridine Y 5- (3- (2,4-Dichlorobenzenesulfonamido) phenoxy)) - 3-chloropyridine.
El compuesto del título se preparó utilizando los métodos descritos en la Patente de los Estados Unidos Núm. 3.576.616. En pocas palabras, a una solución 16,5 M de KOH (2,2 g, 39,6 mmoles) en agua se le añadió 3-nitrofenol (5 g, 36 mmoles) seguido de N-metilpirrolidinona (11 mL) y tolueno (3,6 mL). La mezcla resultante se calentó a 110ºC y el agua se eliminó azeotrópicamente utilizando una trampa Dean-Stark. El exceso de tolueno se eliminó y se recogió en la trampa seguido de la adición de N-metilpirrolidinona (18 mL) y 3,5-dicloropiridina (10,66 g, 72 mmoles, Aldrich) y la mezcla se agitó durante 5 hr a 160ºC. La temperatura se aumentó a 200ºC y la mezcla se agitó durante 15 hr adicionales. La mezcla de reacción bruta se enfrió, se añadió agua (100 mL) seguido de EtOAc (100 mL). La mezcla se filtró a través de un lecho de Celite®, las fases se separaron, y la fase acuosa se extrajo 3x con EtOAc (100 mL). Las fases orgánicas se combinaron y se lavaron dos veces con agua (100 mL), una vez con salmuera (100 mL), se secaron sobre Na_{2}SO_{4}, y se concentraron a vacío. El sólido bruto se purificó mediante cromatografía (EtOAc al 10-25% en hexanos como eluyente) para proporcionar 3,8 g (42%) de producto en forma de un sólido de color naranja.The title compound was prepared using the methods described in United States Patent No. 3,576,616. Simply put, to a 16.5 M solution of KOH (2.2 g, 39.6 mmol) in water was added 3-nitrophenol (5 g, 36 mmol) followed by N-methylpyrrolidinone (11 mL) and toluene (3.6 mL). The resulting mixture was heated to 110 ° C and water was removed azeotropically using a trap Dean-Stark The excess toluene was removed and picked up in the trap followed by the addition of N-methylpyrrolidinone (18 mL) and 3,5-dichloropyridine (10.66 g, 72 mmol, Aldrich) and The mixture was stirred for 5 hr at 160 ° C. The temperature was increased to 200 ° C and the mixture was stirred for an additional 15 hr. The mixture of crude reaction was cooled, water (100 mL) was added followed by EtOAc (100 mL). The mixture was filtered through a bed of Celite®, the phases were separated, and the aqueous phase was extracted 3x with EtOAc (100 mL) The organic phases were combined and washed twice with water (100 mL), once with brine (100 mL), dried over Na 2 SO 4, and concentrated in vacuo. The gross solid is purified by chromatography (10-25% EtOAc in hexanes as eluent) to provide 3.8 g (42%) of product in Shape of an orange solid.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,52 (d, J = 1,9 Hz, 1H), 8,41 (d, J = 2,4 Hz, 1H), 8,08 (ddd, J = 8,2, 2,5, 0,98 Hz, 1H), 7,91 (dd, J = 2,4, 2,3 Hz, 1H), 7,83 (dd, J = 2,3, 2,2 Hz, 1H), 7,72 (dd, J = 8,3, 8,1 Hz, 1H), 7,62 (ddd, J = 8,2, 2,5, 0,98 Hz, 1H).1 H NMR (400 MHz, DMSO-d_6) δ 8.52 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 2.4 Hz, 1H), 8.08 (ddd, J = 8.2, 2.5, 0.98 Hz, 1H), 7.91 (dd, J = 2.4, 2.3 Hz, 1H), 7.83 (dd, J = 2.3, 2.2 Hz, 1H), 7.72 (dd, J = 8.3, 8.1 Hz, 1H), 7.62 (ddd, J = 8.2, 2.5, 0.98 Hz, 1 HOUR).
MS (IE): m/z 253 (37, M+H), 251 (100, M+H).MS (IE): m / z 253 (37, M + H), 251 (100, M + H).
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La 5-(3-aminofenoxi)-3-cloropiridina se sintetizó (100%) de una manera similar a la descrita en el Ejemplo 35.3.The 5- (3-aminophenoxy) -3-chloropyridine it was synthesized (100%) in a manner similar to that described in the Example 35.3.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 8,38 (d, J = 2,2 Hz, 1H), 8,3 (d, J = 2,1 Hz, 1H), 7,53 (dd, J = 2,3, 2,3 Hz, 1H), 7,02 (dd, J = 8,1, 8,0 Hz, 1H), 6,4 (ddd, J = 8,1, 2,1, 1,2 Hz, 1H), 6,24 (dd, J = 2,2, 2,2 Hz, 1H), 6,2 (ddd, J = 8,0, 2,3, 1,4 Hz, 1H), 5,31 (s, 2H).1 H NMR (400 MHz, DMSO-d_ {6}) δ 8.38 (d, J = 2.2 Hz, 1H), 8.3 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 2.3, 2.3 Hz, 1H), 7.02 (dd, J = 8.1, 8.0 Hz, 1H), 6.4 (ddd, J = 8.1, 2.1, 1.2 Hz, 1H), 6.24 (dd, J = 2.2, 2.2 Hz, 1H), 6.2 (ddd, J = 8.0, 2.3, 1.4 Hz, 1H), 5.31 (s, 2H).
MS (IE): m/z 223 (37, M+H), 221 (100, M+H).MS (IE): m / z 223 (37, M + H), 221 (100, M + H).
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La 5-(3-(2,4-diclorobencenosulfonamido)fenoxi))-3-cloropiridina se sintetizó (70%) de una manera similar a la descrita en el Ejemplo 35.4.The 5- (3- (2,4-dichlorobenzenesulfonamido) phenoxy)) - 3-chloropyridine it was synthesized (70%) in a manner similar to that described in the Example 35.4.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 10,91 (s, 1H), 8,46 (d, J = 1,8 Hz, 1H), 8,26 (d, J = 2,6 Hz, 1H), 7,98 (d, J = 8,5 Hz, 1H), 7,87 (d, J = 1,5 Hz, 1H), 7,6 (dd, J = 8,5, 2,2 Hz, 1H), 7,53 (dd, J = 2,3, 2,2 Hz, 1H), 7,29 (dd, J = 8,4, 8,3 Hz, 1H), 6,94-6,9 (m, 1H), 6,8-6,74 (m, 2H).1 H NMR (400 MHz, DMSO-d_ {6} δ 10.91 (s, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.6 (dd, J = 8.5, 2.2 Hz, 1H), 7.53 (dd, J = 2.3, 2.2 Hz, 1H), 7.29 (dd, J = 8.4, 8.3 Hz, 1H), 6.94-6.9 (m, 1H), 6.8-6.74 (m, 2H).
MS (IE): m/z 435 (5, M+H), 434 (7, M+H), 433 (36, M+H), 432 (20, M+H), 431 (100, M+H), 430 (20, M+H), 429 (90, M+H).MS (IE): m / z 435 (5, M + H), 434 (7, M + H), 433 (36, M + H), 432 (20, M + H), 431 (100, M + H), 430 (20, M + H), 429 (90, M + H).
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La 5-(3-(4-metoxibencenosulfonamido)fenoxi))-3-cloropiridina se sintetizó (79%) de una manera similar a la descrita en el Ejemplo 35.4.The 5- (3- (4-methoxybenzenesulfonamido) phenoxy)) - 3-chloropyridine it was synthesized (79%) in a manner similar to that described in the Example 35.4.
RMN H^{1} (400 MHz, DMSO-d_{6}) \delta 10,31 (s, 1H), 8,45 (d, J = 1,8 Hz, 1H), 8,25 (d, J = 2,5 Hz, 1H), 7,66 (d, J = 8,8 Hz, 2H), 7,53 (dd, J = 2,2, 2,2 Hz, 1H), 7,28 (dd, J = 9, 7,3 Hz, 1H), 7,06 (d, J = 9,0 Hz, 2H), 6,92 (dd, J = 8, 1,3 Hz, 1H), 6,79-6,73 (m, 2H), 3,8 (s, 3H).1 H NMR (400 MHz, DMSO-d_ {6} δ 10.31 (s, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.53 (dd, J = 2.2, 2.2 Hz, 1H), 7.28 (dd, J = 9, 7.3 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.92 (dd, J = 8, 1.3 Hz, 1H), 6.79-6.73 (m, 2H), 3.8 (s, 3H).
MS (IE): m/z 395 (5, M+H), 394 (15, M+H), 393 (60, M+H), 392 (30, M+H), 391 (100, M+H).MS (IE): m / z 395 (5, M + H), 394 (15, M + H), 393 (60, M + H), 392 (30, M + H), 391 (100, M + H).
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Éste ilustra la síntesis de 2'-(5-cloro-3-piridiloxi)-5'-(2,4-diclorobencenosulfonamido)-1-feniletanona.This one illustrates the synthesis of 2 '- (5-Chloro-3-pyridyloxy) -5' - (2,4-dichlorobenzenesulfonamido) -1-phenylethanone.
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Se disolvieron 2-fluoro-5-nitroacetofenona (3,6 g, 20 mmoles, descrita por Cooper, et. al. J. Med. Chem. 33:1246-1252 (1990)) y 5-cloro-3-piridinol (3,2 g, 25 mmoles) en acetona (20 mL). Después de la adición de K_{2}CO_{3} sólido (3,5 g, 26 mmoles), la mezcla de reacción se calentó a reflujo durante 4 hr. La mezcla de reacción se enfrió y la acetona se eliminó a presión reducida. El residuo se suspendió en agua desionizada (50 mL) y se extrajo con acetato de etilo (3 x 50 mL). Las porciones orgánicas combinadas se lavaron con salmuera saturada, se secaron sobre MgSO_{4}, se filtraron, y se concentraron hasta un aceite de color pardo que se purificó parcialmente mediante cromatografía en columna (gel de sílice, hexanos:acetato de etilo 4:1) para proporcionar 4 g de 2'-(5-cloro-3-piridiloxi)-5'-nitro-1-feniletanona. Esta sustancia se disolvió en etanol (40 mL) y ácido acético (5,3 mL, 93 mmoles) a lo que se añadió polvo de hierro (malla 300, 2,6 g, 46,5 mmoles). La mezcla de reacción se calentó a reflujo durante dos días. Después de la eliminación del hierro en exceso (con un recuperador de varilla de agitación magnética), la mezcla de reacción se vertió en 300 mL de agua desionizada y se extrajo con acetato de etilo (3 x 100 mL). Las porciones orgánicas combinadas se lavaron con salmuera saturada, se secaron sobre MgSO_{4}, se filtraron, y se concentraron hasta un aceite de color pardo que se purificó mediante cromatografía en columna (gel de sílice, hexanos:acetato de etilo 4:1). La 5'-amino-2'-(5-cloro-3-piridiloxi)-1-feniletanona producto se obtuvo en forma de un aceite de color amarillo (1,03 g).2-Fluoro-5-nitroacetophenone (3.6 g, 20 mmol, described by Cooper, et. Al . J. Med. Chem. 33: 1246-1252 (1990)) and 5-chloro-3-pyridinol ( 3.2 g, 25 mmol) in acetone (20 mL). After the addition of solid K2CO3 (3.5 g, 26 mmol), the reaction mixture was heated at reflux for 4 hr. The reaction mixture was cooled and the acetone was removed under reduced pressure. The residue was suspended in deionized water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil that was partially purified by column chromatography (silica gel, hexanes: ethyl acetate 4: 1) to provide 4 g of 2 '- (5-chloro-3-pyridyloxy) -5'-nitro-1-phenyletanone. This substance was dissolved in ethanol (40 mL) and acetic acid (5.3 mL, 93 mmol) to which iron powder (300 mesh, 2.6 g, 46.5 mmol) was added. The reaction mixture was heated at reflux for two days. After removal of excess iron (with a magnetic stir bar recovery), the reaction mixture was poured into 300 mL of deionized water and extracted with ethyl acetate (3 x 100 mL). The combined organic portions were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a brown oil that was purified by column chromatography (silica gel, hexanes: ethyl acetate 4: 1 ). The product 5'-amino-2 '- (5-chloro-3-pyridyloxy) -1-phenyletanone was obtained as a yellow oil (1.03 g).
MS ESI m/e: 262,9 (M + H).MS ESI m / e: 262.9 (M + H).
Se combinaron 5'-amino-2'-(5-cloro-3-piridiloxi)-1-feniletanona (100 mg, 0,38 mmoles), 2,6-lutidina (49 \muL, 0,42 mmoles), DMAP (2 mg, 0,019 mmoles), y cloruro de 2,4-diclorobencenosulfonilo (103 mg, 0,42 mmoles) en CH_{2}Cl_{2} (2 mL) a temperatura ambiente. Al cabo de 14 h, la mezcla de reacción se purificó directamente mediante cromatografía radial (Chromatatron, capa de 2 mm gel de sílice, hexanos:acetato de etilo 2:1 con MeOH al 0,25%) para producir el producto del título en forma de un aceite transparente que se solidificó al reposar (144 mg).They combined 5'-amino-2 '- (5-chloro-3-pyridyloxy) -1-phenyletanone (100 mg, 0.38 mmol), 2,6-lutidine (49 µL, 0.42 mmol), DMAP (2 mg, 0.019 mmol), and chloride 2,4-dichlorobenzenesulfonyl (103 mg, 0.42 mmol) in CH 2 Cl 2 (2 mL) at room temperature. After 2 pm, the reaction mixture was purified directly by chromatography radial (Chromatatron, 2 mm layer silica gel, hexanes: acetate ethyl 2: 1 with 0.25% MeOH) to produce the title product in the form of a transparent oil that solidified on standing (144 mg)
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,40 (bs, 1H); 8,25 (bs, 1H); 7,96 (d, J= 8,6 Hz, 1H); 7,55 (m, 2H); 7,50 (s,1H); 7,25-7,38 (m, 2H); 7,24 (d, J= 8,6 Hz, 1H); 6,85 (d, J= 6,7 Hz, 1H); 2,54 (s, 3H).1 H NMR (400 MHz) (CDCl 3) δ 8.40 (bs, 1H); 8.25 (bs, 1H); 7.96 (d, J = 8.6 Hz, 1H); 7.55 (m, 2H); 7.50 (s, 1 H); 7.25-7.38 (m, 2H); 7.24 (d, J = 8.6 Hz, 1H); 6.85 (d, J = 6.7 Hz, 1H); 2.54 (s, 3 H).
MS ESI m/e: 470,6 (M – H).MS ESI m / e: 470.6 (M-H).
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Este ejemplo ilustra la síntesis de ácido etil-2-(3-cloro-5-piridiloxi)-5-(2,4-diclorofenilamino-sulfonil)benzoico.This example illustrates the synthesis of acid ethyl-2- (3-chloro-5-pyridyloxy) -5- (2,4-dichlorophenylamino-sulfonyl) benzoic acid.
La anilina preparada en el Ejemplo 1 (250 mg, 0,86 mmoles) se convirtió en el cloruro de sulfonilo correspondiente utilizando el procedimiento de R. V. Hoffman (Org. Sin. Coll. Vol. VII, 508-511), para proporcionar 196 mg (61%) de producto en forma de un sólido de color blanco.The aniline prepared in Example 1 (250 mg, 0.86 mmol) became the corresponding sulfonyl chloride using the procedure of R. V. Hoffman (Org. Sin. Coll. Vol. VII, 508-511), to provide 196 mg (61%) of product in the form of a white solid.
MS ESI m/e: 376,0 (M + H).MS ESI m / e: 376.0 (M + H).
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El cloruro de sulfonilo preparado antes (40 mg, 0,11 mmoles), 2,4-dicloroanilina (83 mg, 0,22 mmoles), y MeOH (2,0 mL) se combinaron y se agitaron a temperatura ambiente durante 4,0 hr. La mezcla de reacción se concentró a vacío, y el residuo se disolvió en CH_{2}Cl_{2}, y se lavó con HCl acuoso 1 N y salmuera. La solución orgánica resultante se secó sobre MgSO_{4} y se concentró para dar un aceite de color amarillo. El producto bruto se purificó utilizando HPLC en fase reversa (empaquetamiento C_{18}, CH_{3}CN al 5-95% en H_{2}O). Las fracciones que contenían el producto se liofilizaron para proporcionar 19 mg (36%) de un sólido de color blanco. pf 153-155ºC.The sulfonyl chloride prepared before (40 mg, 0.11 mmol), 2,4-dichloroaniline (83 mg, 0.22 mmol), and MeOH (2.0 mL) were combined and stirred at temperature ambient for 4.0 hr. The reaction mixture was concentrated to vacuum, and the residue was dissolved in CH2Cl2, and washed with 1N aqueous HCl and brine. The resulting organic solution was dried over MgSO4 and concentrated to give a colored oil yellow. The crude product was purified using phase HPLC reverse (packing C 18, CH 3 CN at 5-95% in H2O). The fractions that contained the product was lyophilized to provide 19 mg (36%) of a solid White color. mp 153-155 ° C.
RMN H^{1} (400 MHz) (CD_{3}OD) \delta 8,35 (1H, d, J=2,0 Hz); 8,20 (2H, d, J=2,4 Hz); 7,91 (1H, dd, J_{1}=8,7 Hz J_{2}=2,4 Hz); 7,55 (1H, d, J=8,7 Hz); 7,45 (1H, dd, J_{1}=4,5 Hz, J_{2}=2,3 Hz); 7,40 (1H, d, J=2,3 Hz); 7,35 (1H, dd, J_{1}=8,7 Hz J_{2}=2,4 Hz); 7,26 (1H, d, J=8,6 Hz); 4,23 (2H, q, J=7,2 Hz); 1,20 (3H, t, J=7,2 Hz).1 H NMR (400 MHz) (CD 3 OD) δ 8.35 (1H, d, J = 2.0 Hz); 8.20 (2H, d, J = 2.4 Hz); 7.91 (1H, dd, J1 = 8.7 Hz J2 = 2.4 Hz); 7.55 (1H, d, J = 8.7 Hz); 7.45 (1H, dd, J1 = 4.5 Hz, J2 = 2.3 Hz); 7.40 (1H, d, J = 2.3 Hz); 7.35 (1H, dd, J1 = 8.7 Hz J2 = 2.4 Hz); 7.26 (1H, d, J = 8.6 Hz); 4.23 (2H, q, J = 7.2 Hz); 1.20 (3H, t, J = 7.2 Hz).
MS ESI m/e: 501,0 (M + H).MS ESI m / e: 501.0 (M + H).
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Este ejemplo ilustra la síntesis de 5-(2,4-diclorobenzamido)-2-(3-cloro-5-piridiloxi)benzoato de etilo.This example illustrates the synthesis of 5- (2,4-dichlorobenzamido) -2- (3-chloro-5-pyridyloxy) benzoate of ethyl.
A una solución de la anilina producida en el Ejemplo 1 (100 mg, 0,34 mmoles) en CH_{2}Cl_{2} (2 mL) se le añadió piridina (81 \muL, 1 mmoles) y cloruro de 2,4-diclorobenzoilo (140 mg, 0,68 mmoles). La mezcla se agitó durante 90 min. El producto se purificó mediante cromatografía en columna sobre gel de sílice (elución en gradiente: hexano/acetato de etilo 30:1 a hexano/acetato de etilo 7:1) seguido de recristalización en CH_{2}Cl_{2}/hexanos para producir 126 mg (79%) del compuesto del título. pf 125-127ºC.To a solution of the aniline produced in the Example 1 (100 mg, 0.34 mmol) in CH 2 Cl 2 (2 mL) was given added pyridine (81 µL, 1 mmol) and chloride 2,4-dichlorobenzoyl (140 mg, 0.68 mmol). Mix stirred for 90 min. The product was purified by column chromatography on silica gel (gradient elution: hexane / ethyl acetate 30: 1 to hexane / ethyl acetate 7: 1) followed recrystallization from CH2Cl2 / hexanes to produce 126 mg (79%) of the title compound. mp 125-127 ° C.
RMN H^{1} (400 MHz) (CD_{3}CN) \delta 8,95 (bs, 1H); 8,28 (dd, J= 11,4, 2,0 Hz, 2H); 8,20 (d, J= 2,4 Hz, 1H); 7,90 (dd, J= 8,8, 2,7 Hz, 1H); 7,60 (d, J= 8,0 Hz, 2H); 7,46 (dd, J= 8,2, 2,0 Hz, 1H); 7,26 (t, J= 2,3 Hz, 1H); 7,21 (d, J= 8,8 Hz, 1H); 4,19 (q, J= 7,2 Hz, 2H); 1,13 (t, J= 7,2 Hz, 3H).1 H NMR (400 MHz) (CD 3 CN) δ 8.95 (bs, 1H); 8.28 (dd, J = 11.4, 2.0 Hz, 2H); 8.20 (d, J = 2.4 Hz, 1H); 7.90 (dd, J = 8.8, 2.7 Hz, 1H); 7.60 (d, J = 8.0 Hz, 2H); 7.46 (dd, J = 8.2, 2.0 Hz, 1H); 7.26 (t, J = 2.3 Hz, 1H); 7.21 (d, J = 8.8 Hz, 1H); 4.19 (q, J = 7.2 Hz, 2H); 1.13 (t, J = 7.2 Hz, 3H).
MS ESI m/e: 465,0 (M + H).MS ESI m / e: 465.0 (M + H).
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Este ejemplo ilustra la preparación de 4-(3-cloro-5-piridiloxi)-3-(4-trifluorometilbenceno-sulfonamido)benzotrifluoruro.This example illustrates the preparation of 4- (3-Chloro-5-pyridyloxy) -3- (4-trifluoromethylbenzene sulfonamido) benzotrifluoride.
Utilizando el método del Ejemplo 21.2, 4-fluoro-3-nitrobenzotrifluoruro (7,4 g) y 3-cloro-5-hidroxipiridina (4,59 g) se calentaron con carbonato de potasio (5,4 g) en DMF a 80ºC durante 1 h, después 60º durante la noche. La elaboración produjo el compuesto del título (10,9 g) en forma de un sólido de color amarillo.Using the method of Example 21.2, 4-fluoro-3-nitrobenzotrifluoride (7.4 g) and 3-chloro-5-hydroxypyridine (4.59 g) were heated with potassium carbonate (5.4 g) in DMF at 80 ° C for 1 h, then 60 ° overnight. The elaboration produced the title compound (10.9 g) as a solid of yellow color.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,491 (d, J=2 Hz, 1H); 8,359 (d, J=2,8 Hz, 1H); 8,30 (d, J=2 Hz, 1H); 7,847 (dd, J=8,8, 2 Hz, 1H); 7,425 (t, J= 2,4 Hz, 1H); 7,185 (d, J=8 Hz, 1H).1 H NMR (400 MHz) (CDCl 3) δ 8.491 (d, J = 2 Hz, 1H); 8.359 (d, J = 2.8 Hz, 1H); 8.30 (d, J = 2 Hz, 1H); 7.847 (dd, J = 8.8, 2 Hz, 1H); 7.425 (t, J = 2.4 Hz, 1H); 7.185 (d, J = 8 Hz, 1H).
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Utilizando el método del Ejemplo 17.3, el 4-(3-cloro-5-piridiloxi)-3-nitrobenzotrifluoruro (10,9 g) se redujo hasta el compuesto del título (9,5 g) que se obtuvo en forma de un sólido de color tostado claro. pf 117-120ºC.Using the method of Example 17.3, the 4- (3-Chloro-5-pyridyloxy) -3-nitrobenzotrifluoride (10.9 g) was reduced to the title compound (9.5 g) which was obtained in the form of a light tan solid. pf 117-120 ° C.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,35 (br s, 2H); 7,267 (m, 1H); 7,085 (d, J=1,8 Hz, 1H); 6,922 (dd, J=8,4, 1,4 Hz, 1H); 6,922 (d, J= 8,4 Hz, 1H); 3,90 (br s, 2H).1 H NMR (400 MHz) (CDCl 3) δ 8.35 (br s, 2H); 7.267 (m, 1 H); 7.085 (d, J = 1.8 Hz, 1H); 6,922 (dd, J = 8.4, 1.4 Hz, 1H); 6,922 (d, J = 8.4 Hz, 1H); 3.90 (br s, 2H).
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Utilizando el método del Ejemplo 17.4, se combinaron 4-(3-cloro-5-piridiloxi)-3-aminobenzotrifluoruro (0,4 g) y cloruro de 4-trifluorometilbencenosulfonilo (0,339 g) para proporcionar, después de la trituración con éter, la sulfonamida del título (0,198 g) que se obtuvo en forma de un sólido cristalino. pf 169-171ºC.Using the method of Example 17.4, combined 4- (3-Chloro-5-pyridyloxy) -3-aminobenzotrifluoride (0.4 g) and chloride 4-trifluoromethylbenzenesulfonyl (0.339 g) for provide, after trituration with ether, sulfonamide of the title (0.198 g) that was obtained as a crystalline solid. mp 169-171 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 10,728 (s, 1H); 8,398 (d, J=1,6 Hz, 1H); 8,022 (d, J=2,4 Hz, 1H); 7,916 (d, J=8,4 Hz, 2H); 7,862 (d, J=8,8 Hz, 2H); 7,687 (d, J= 2,4 Hz, 1H); 7,59 (dd, J=8,8, 2,4 Hz, 1H); 7,253 (t, J= 2,2 Hz, 1H); 7,182 (d, J=8,8 Hz, 1H).1 H NMR (400 MHz) (DMSO) δ 10.728 (s, 1H); 8.398 (d, J = 1.6 Hz, 1H); 8.022 (d, J = 2.4 Hz, 1H); 7,916 (d, J = 8.4 Hz, 2H); 7.862 (d, J = 8.8 Hz, 2H); 7.687 (d, J = 2.4 Hz, 1H); 7.59 (dd, J = 8.8, 2.4 Hz, 1H); 7.253 (t, J = 2.2 Hz, 1H); 7.182 (d, J = 8.8 Hz, 1H).
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Este ejemplo ilustra la preparación de 4-(3-cloro-5-piridiloxi)-3-(2,4-diclorobencenosulfonamido)-benzotrifluoruro.This example illustrates the preparation of 4- (3-Chloro-5-pyridyloxy) -3- (2,4-dichlorobenzenesulfonamido) -benzotrifluoride.
Utilizando el método del Ejemplo 17.4, se combinaron 4-(3-cloro-5-piridiloxi)-3-aminobenzotrifluoruro (0,4 g) y cloruro de 2,4-diclorobencenosulfonilo (0,38 g) para proporcionar el compuesto del título (0,26 g), en forma de un sólido cristalino después de la cromatografía instantánea y la trituración con éter. pf 150-151,5ºC.Using the method of Example 17.4, combined 4- (3-Chloro-5-pyridyloxy) -3-aminobenzotrifluoride (0.4 g) and 2,4-dichlorobenzenesulfonyl chloride (0.38 g) to provide the title compound (0.26 g), in form of a crystalline solid after chromatography snapshot and crushing with ether. pf 150-151.5 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 10,767 (s, 1H); 8,415 (d, J=1,8 Hz, 1H); 7,839 (d, J=8,6 Hz, 1H); 7,713 (d, J=1,8 Hz, 1H); 7,64 (d, J=2 Hz, 1H); 7,611 (dd, J= 8,7, 1,8 Hz, 1H); 7,499 (dd, J=8,6, 2,1 Hz, 1H); 7,235 (d, J=8,5 Hz, 1H); 7,179 (t, J= 2,2 Hz, 1H).1 H NMR (400 MHz) (DMSO) δ 10.767 (s, 1H); 8.415 (d, J = 1.8 Hz, 1H); 7.839 (d, J = 8.6 Hz, 1H); 7.713 (d, J = 1.8 Hz, 1H); 7.64 (d, J = 2 Hz, 1H); 7.611 (dd, J = 8.7, 1.8 Hz, 1H); 7.499 (dd, J = 8.6, 2.1 Hz, 1H); 7.235 (d, J = 8.5 Hz, 1H); 7.179 (t, J = 2.2 Hz, 1H).
C_{18}H_{10}N_{2}F_{3}Cl_{3}SO_{3} calc: %C 43,4 %H 2,03 %N 5,63 encontrado: %C 43,62 %H 1,92 %N 5,60.C_18 H_ {10} N_ {2} F_ {3} Cl_ {3} SO_ {3} calc:% C 43.4% H 2.03% N 5.63 found:% C 43.62% H 1.92% N 5.60.
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Este ejemplo ilustra la preparación de 4-(3-cloro-5-piridiloxi)-3-(4-metoxibencenosulfonamido)-benzotrifluoruro.This example illustrates the preparation of 4- (3-Chloro-5-pyridyloxy) -3- (4-methoxybenzenesulfonamido) -benzotrifluoride.
Utilizando el método del Ejemplo 17.4, se combinaron 4-(3-cloro-5-piridiloxi)-3-aminobenzotrifluoride (0,41 g) y cloruro de 4-metoxibencenosulfonilo (0,30 g) para proporcionar el compuesto del título (0,236 g) en forma de un sólido cristalino después de la cromatografía instantánea y la trituración con éter.Using the method of Example 17.4, combined 4- (3-Chloro-5-pyridyloxy) -3-aminobenzotrifluoride (0.41 g) and 4-methoxybenzenesulfonyl chloride (0.30 g) to provide the title compound (0.236 g) in form of a crystalline solid after chromatography snapshot and crushing with ether.
RMN H^{1} (400 MHz) (DMSO) \delta 10,309 (s, 1H); 8,419 (d, J=2 Hz, 1H); 8,10 (d, J=2,5 Hz, 1H); 7,707 (d, J=2,2 Hz, 1H); 7,613 (d, J=9 Hz, 2H); 7,527 (dd, J= 8,4, 2,2 Hz, 1H); 7,18 (d, J=9,1 Hz, 1H); 7,169 (t, J=2,2 Hz, 1H); 6,978 (d, J= 8,9 Hz, 1H); 3,784 (s, 3H).1 H NMR (400 MHz) (DMSO) δ 10.309 (s, 1H); 8.419 (d, J = 2 Hz, 1H); 8.10 (d, J = 2.5 Hz, 1H); 7.707 (d, J = 2.2 Hz, 1H); 7.613 (d, J = 9 Hz, 2H); 7.527 (dd, J = 8.4, 2.2 Hz, 1H); 7.18 (d, J = 9.1 Hz, 1H); 7.169 (t, J = 2.2 Hz, 1H); 6,978 (d, J = 8.9 Hz, 1H); 3,784 (s, 3 H).
C_{19}H_{14}N_{2}F_{3}ClSO_{4} calc: %C 49,7 %H 3,08 %N 6,11 encontrado: %C 49,84 %H 3,02 %N 6,11.C 19 H 14 N 2 F 3 ClSO 4 calc: % C 49.7% H 3.08% N 6.11 found:% C 49.84% H 3.02% N 6.11.
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Este ejemplo ilustra la preparación de 4-(3-cloro-5-piridiloxi)-3-(4-yodobencenosulfonamido)benzotrifluoruro.This example illustrates the preparation of 4- (3-Chloro-5-pyridyloxy) -3- (4-iodobenzenesulfonamido) benzotrifluoride.
Utilizando el método del Ejemplo 17.4, se combinaron 4-(3-cloro-5-piridiloxi)-3-aminobenzotrifluoride (0,41 g) y cloruro de 4-yodobencenosulfonilo (0,30 g) para proporcionar el compuesto del título (0,34 g) en forma de cristales directamente de la mezcla de reacción. pf 192-193ºC.Using the method of Example 17.4, combined 4- (3-Chloro-5-pyridyloxy) -3-aminobenzotrifluoride (0.41 g) and 4-iodobenzenesulfonyl chloride (0.30 g) to provide the title compound (0.34 g) as crystals directly from the reaction mixture. pf 192-193 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 10,56 (s, 1H); 8,428 (d, J=2,1 Hz, 1H); 8,081 (d, J=2,5 Hz, 1H); 7,847 (d, J=8,5 Hz, 2H); 7,69 (d, J=2,2 Hz, 1H); 7,569 (dd, J= 8,8, 2,2 Hz, 1H); 7,436 (d, J=8,5 Hz, 2H); 7,207 (t, J=2,3 Hz, 1H); 7,204 (d, J= 2,4 Hz, 1H).1 H NMR (400 MHz) (DMSO) δ 10.56 (s, 1H); 8.428 (d, J = 2.1 Hz, 1H); 8.081 (d, J = 2.5 Hz, 1H); 7.847 (d, J = 8.5 Hz, 2H); 7.69 (d, J = 2.2 Hz, 1H); 7.569 (dd, J = 8.8, 2.2 Hz, 1H); 7.436 (d, J = 8.5 Hz, 2H); 7.207 (t, J = 2.3 Hz, 1H); 7.204 (d, J = 2.4 Hz, 1H).
C_{18}H_{11}N_{2}F_{3}ClSO_{3}I calc: %C 38,9 %H 2,00 %N 5,05 encontrado: %C 39,14 %H 1,99 %N 5,05.C 18 H 11 N 2 F 3 ClSO 3 I calc: % C 38.9% H 2.00% N 5.05 found:% C 39.14% H 1.99% N 5.05.
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Éste ilustra la síntesis de 4-(N-oxi-3-cloro-5-piridiloxi)-3-(2,4-diclorobencenosulfonamido)-benzotrifluoruro.This one illustrates the synthesis of 4- (N-oxy-3-chloro-5-pyridyloxy) -3- (2,4-dichlorobenzenesulfonamido) -benzotrifluoride.
Una solución de 4-(3-cloro-5-piridiloxi)-3-(2,4-diclorobencenosulfonamido)-benzotrifluoruro del Ejemplo 43 en cloruro de metileno se trató con ácido 3-cloroperoxibenzoico (aproximadamente 1,2 equiv.) a rt hasta que se completó la reacción. La mezcla de reacción se concentró y el residuo sólido se disolvió en cloruro de metileno y se diluyó con hexano para proporcionar el compuesto del título (0,078 g) en forma de un sólido de color blanco.A solution of 4- (3-Chloro-5-pyridyloxy) -3- (2,4-dichlorobenzenesulfonamido) -benzotrifluoride of Example 43 in methylene chloride was treated with acid 3-Chloroperoxybenzoic acid (approximately 1.2 equiv.) A rt until the reaction is complete. The reaction mixture is concentrated and the solid residue was dissolved in methylene chloride and diluted with hexane to provide the title compound (0.078 g) in the form of a white solid.
RMN H^{1} (400 MHz) (DMSO) \delta 10,80 (s, 1H); 8,323 (t, J=1,5 Hz, 1H); 7,868 (d, J=8,6 Hz, 1H); 7,801 (t, J=1,8 Hz, 1H); 7,737 (d, J=2 Hz, 1H); 7,704 (d, J= 2,5 Hz, 1H); 7,63 (m, 1H); 7,541 (dd, J=8,7, 2,1 Hz, 1H); 7,396 (d, J=8,5 Hz, 1H); 6,781 (t, J= 1,8 Hz, 1H.1 H NMR (400 MHz) (DMSO) δ 10.80 (s, 1H); 8.323 (t, J = 1.5 Hz, 1H); 7.868 (d, J = 8.6 Hz, 1H); 7.801 (t, J = 1.8 Hz, 1H); 7.737 (d, J = 2 Hz, 1H); 7.704 (d, J = 2.5 Hz, 1H); 7.63 (m, 1 H); 7.541 (dd, J = 8.7, 2.1 Hz, 1H); 7.396 (d, J = 8.5 Hz, 1H); 6.781 (t, J = 1.8 Hz, 1H.
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Este ejemplo ilustra la preparación de 2-(3-cloro-5-piridiloxi)-5-(2,4-diclorobencenosulfonamido)-benzotrifluoruro.This example illustrates the preparation of 2- (3-Chloro-5-pyridyloxy) -5- (2,4-dichlorobenzenesulfonamido) -benzotrifluoride.
Utilizando el método del Ejemplo 21.2, se combinaron 2-fluoro-5-nitrobenzotrifluoruro (5,0 g) y 3-cloro-5-hidroxipiridina (3,1 g) con carbonato de potasio (5,4 g) en DMF y se calentaron durante la noche a 60ºC. La elaboración produjo el compuesto del título (8,4 g) en forma de un sólido bruto de color amarillo que se utilizó directamente en la siguiente reacción.Using the method of Example 21.2, combined 2-fluoro-5-nitrobenzotrifluoride (5.0 g) and 3-chloro-5-hydroxypyridine (3.1 g) with potassium carbonate (5.4 g) in DMF and heated overnight at 60 ° C. The elaboration produced the compound of title (8.4 g) in the form of a crude yellow solid that is used directly in the next reaction.
RMN H^{1} (400 MHz) (CDCl_{3}) \delta 8,65 (br d, J=2,6 Hz, 1H); 8,558 (br s, 1H); 8,41 (dd, J= 9, 2,6 Hz, 1H); 8,403 (br s, 1H); 7,42 (t, J= 2,2 Hz, 1H); 7,039 (d, J= 9,2 Hz, 1H).1 H NMR (400 MHz) (CDCl 3) δ 8.65 (br d, J = 2.6 Hz, 1H); 8,558 (br s, 1 H); 8.41 (dd, J = 9, 2.6 Hz, 1H); 8.403 (br s, 1 H); 7.42 (t, J = 2.2 Hz, 1H); 7.039 (d, J = 9.2 Hz, 1H).
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Utilizando el método del Ejemplo 17.3, se redujo 2-(3-cloro-5-piridiloxi)-5-nitrobenzotrifluoruro (8,4 g brutos) al compuesto del título (7,5 g) que se obtuvo en forma de un aceite de color naranja y se utilizó directamente en reacciones adicionales.Using the method of Example 17.3, it was reduced 2- (3-Chloro-5-pyridyloxy) -5-nitrobenzotrifluoride (8.4 g gross) to the title compound (7.5 g) obtained in form of an orange oil and was used directly in additional reactions
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Utilizando el método del Ejemplo 17.4, se combinaron 2-(3-cloro-5-piridiloxi)-5-aminobenzotrifluoruro (0,394 g) y cloruro de 2,4-diclorobencenosulfonilo (0,34 g) para proporcionar, después de la cromatografía instantánea y la trituración con hexano/éter el compuesto del título en forma de un sólido cristalino (0,146 g). pf 129-130ºC.Using the method of Example 17.4, combined 2- (3-Chloro-5-pyridyloxy) -5-aminobenzotrifluoride (0.394 g) and 2,4-dichlorobenzenesulfonyl chloride (0.34 g) to provide, after flash chromatography and trituration with hexane / ether the title compound as a crystalline solid (0.146 g). mp 129-130 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 11,124 (s, 1H); 8,452 (d, J=1,8 Hz, 1H); 8,304 (d, J=2,5 Hz, 1H); 8,05 (d, J= 8,5 Hz, 1H); 7,91 (d, J=2,1 Hz, 1H); 7,664 (t, J= 2,3 Hz, 1H); 7,651 (dd, J= 8,8, 2,6 Hz, 1H); 7,476 (d, J=2,6 Hz, 1H); 7,365 (dd, J=8,8, 2,6 Hz, 1H); 7,196 (d, J=8,9 Hz, 1H).1 H NMR (400 MHz) (DMSO) δ 11.124 (s, 1H); 8.452 (d, J = 1.8 Hz, 1H); 8.304 (d, J = 2.5 Hz, 1H); 8.05 (d, J = 8.5 Hz, 1H); 7.91 (d, J = 2.1 Hz, 1H); 7.664 (t, J = 2.3 Hz, 1H); 7.651 (dd, J = 8.8, 2.6 Hz, 1H); 7.476 (d, J = 2.6 Hz, 1H); 7.365 (dd, J = 8.8, 2.6 Hz, 1H); 7.196 (d, J = 8.9 Hz, 1H).
C_{18}H_{10}N_{2}F_{3}Cl_{3}SO_{3} calc: %C 43,4 %H 2,03 %N 5,63 encontrado: %C 43,35 %H 2,06 %N 5,53.C_18 H_ {10} N_ {2} F_ {3} Cl_ {3} SO_ {3} calc:% C 43.4% H 2.03% N 5.63 found:% C 43.35% H 2.06% N 5.53.
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Este ejemplo ilustra la preparación de 2-(3-cloro-5-piridiloxi)-5-(4-metiltiobencenosulfonamido)-benzotrifluoruro.This example illustrates the preparation of 2- (3-Chloro-5-pyridyloxy) -5- (4-methylthiobenzenesulfonamido) -benzotrifluoride.
Utilizando el método del Ejemplo 17.4, se combinaron 2-(3-cloro-5-piridiloxi)-5-aminobenzotrifluoruro (0,394 g) y cloruro de 4-metiltiobencenosulfonilo (0,34 g) [H. Burton, et al. J. Chem. Soc. 1948, 604-605] para proporcionar, después de la cromatografía instantánea y la trituración con hexano/éter, el compuesto del título en forma de cristales (0,22 g). pf 109,5-111ºC.Using the method of Example 17.4, 2- (3-chloro-5-pyridyloxy) -5-aminobenzotrifluoride (0.394 g) and 4-methylthiobenzenesulfonyl chloride (0.34 g) [H. Burton, et al . J. Chem. Soc. 1948, 604-605] to provide, after flash chromatography and trituration with hexane / ether, the title compound as crystals (0.22 g). mp 109.5-111 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 10,603 (s, 1H); 8,451 (br s, 1H); 8,302 (d, J=2,4 Hz, 1H); 7,653 (d, J= 8,2 Hz, 2H); 7,467 (d, J=2,3 Hz, 1H); 7,406 (d, J= 8,4 Hz, 2H); 7,361 (dd, J= 8,9, 2,5 Hz, 1H); 7,197 (d, J=8,8 Hz, 1H); 2,50 (s, 3H).1 H NMR (400 MHz) (DMSO) δ 10.603 (s, 1H); 8,451 (br s, 1 H); 8.302 (d, J = 2.4 Hz, 1H); 7.653 (d, J = 8.2 Hz, 2H); 7.467 (d, J = 2.3 Hz, 1H); 7.406 (d, J = 8.4 Hz, 2H); 7.361 (dd, J = 8.9, 2.5 Hz, 1H); 7.197 (d, J = 8.8 Hz, 1H); 2.50 (s, 3H).
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Este ejemplo ilustra la preparación de 2-(3-cloro-5-piridiloxi)-5-(4-metilsulfinilbencenosulfonamido)-benzotrifluoruro.This example illustrates the preparation of 2- (3-Chloro-5-pyridyloxy) -5- (4-methylsulfinylbenzenesulfonamido) -benzotrifluoride.
A una solución de 2-(3-cloro-5-piridiloxi)-5-(4-metiltiobencenosulfonamido)benzotrifluoruro (0,21 g) en acetona (5 mL) se le añadió Oxone^{TM} (0,136 g) en agua (1 mL). Al cabo de 5 hr, la mezcla de reacción se filtró, y el producto filtrado se diluyó en cloruro de metileno y se extrajo con agua. Los sólidos del extracto orgánico se purificaron mediante cromatografía sobre sílice. La trituración con hexano produjo el sulfóxido del título (0,144 g) en forma de un sólido de color blanco. pf 156-159ºC.To a solution of 2- (3-Chloro-5-pyridyloxy) -5- (4-methylthiobenzenesulfonamido) benzotrifluoride (0.21 g) in acetone (5 mL), Oxone ™ (0.136 g) was added in water (1 mL). After 5 hr, the reaction mixture was filtered, and the Filtrate was diluted in methylene chloride and extracted with Water. The solids of the organic extract were purified by chromatography on silica. Crushing with hexane produced the title sulfoxide (0.144 g) in the form of a colored solid White. mp 156-159 ° C.
RMN H^{1} (400 MHz) (DMSO) \delta 10,73 (s, 1H); 8,46 (d, J=1,8 Hz, 1H); 8,312 (d, J=2,6 Hz, 1H); 7,946 (d, J= 8,6 Hz, 2H); 7,891 (d, J=8,2 Hz, 2H); 7,674 (t, J=2,3 Hz, 1H); 7,452 (d, J= 2,6 Hz, 1H); 7,39 (dd, J= 9,1, 2,6 Hz, 1H); 7,211 (d, J=9,1 Hz, 1H); 2,775 (s, 3H).1 H NMR (400 MHz) (DMSO) δ 10.73 (s, 1H); 8.46 (d, J = 1.8 Hz, 1H); 8.312 (d, J = 2.6 Hz, 1H); 7,946 (d, J = 8.6 Hz, 2H); 7.891 (d, J = 8.2 Hz, 2H); 7.674 (t, J = 2.3 Hz, 1H); 7.452 (d, J = 2.6 Hz, 1H); 7.39 (dd, J = 9.1, 2.6 Hz, 1H); 7.211 (d, J = 9.1 Hz, 1H); 2,775 (s, 3 H).
C_{19}H_{14}N_{2}F_{3}ClS_{2}O_{4} calc: %C 46,4 %H 2,87 %N 5,71 encontrado: %C 46,54 %H 2,89 %N 5,64.C_ {19} H_ {14} N_ {2} F_ {3} ClS_ {O} {4} calc:% C 46.4% H 2.87% N 5.71 found:% C 46.54% H 2.89% N 5.64.
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Utilizando métodos similares a Lehmann, et al., ídem., los compuestos seleccionados mostraron los siguientes valores de CI_{50} en un análisis de unión al ligando PPAR\gamma utilizando BRL 49653-[^{3}H] como radioligando. Los valores de CI_{50} se definen como la concentración de compuestos de ensayo requerida para reducir la unión específica de BRL 49653-[^{3}H] en 50%.Using methods similar to Lehmann, et al ., Idem ., The selected compounds showed the following IC 50 values in a PPAR? Ligand binding analysis using BRL 49653 - [3 H] as radioligand. IC 50 values are defined as the concentration of test compounds required to reduce the specific binding of BRL 49653 - [3 H] by 50%.
Claims (31)
- \quadquad
- R^{12} es hidrógeno o alquilo C_{1}-C_{10}; y el subíndice m es un número entero de 0 a 2;R 12 is hydrogen or alkyl C 1 -C 10; and the subscript m is a number integer from 0 to 2;
- \quadquad
- R^{1} es alquilo C_{1}-C_{10}, haloalquilo C_{1}-C_{10}, -C(O)R^{14}, -CO_{2}R^{14} o -C(O)NR^{15}R^{16},R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -C (O) R 14, -CO 2 R 14 or -C (O) NR 15 R 16,
- \quadquad
- R^{14} es hidrógeno o alquilo C_{1}-C_{10};R 14 is hydrogen or alkyl C 1 -C 10;
- \quadquad
- R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10};R 15 and R 16 are each independently hydrogen or C 1 -C 10 alkyl;
- \quadquad
- R^{2} es fenilo sustituido opcionalmente con uno a tres sustituyentes seleccionados independientemente entre halógeno, -OCF_{3}, -OH, -O-alquilo C_{1}-C_{8}, -C(O)-alquilo C_{1}-C_{8}, -CN, -CF_{3}, -alquilo C_{1}-C_{8} y NH_{2}R2 is phenyl optionally substituted with one to three substituents independently selected from halogen, -OCF 3, -OH, -O-alkyl C_ {1} -C_ {8}, -C (O) -alkyl C 1 -C 8, -CN, -CF 3, -alkyl C 1 -C 8 and NH 2
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- \quadquad
- R^{12} es hidrógeno o alquilo C_{1}-C_{10}; y el subíndice m es un número entero de 0 a 2;R 12 is hydrogen or alkyl C 1 -C 10; and the subscript m is a number integer from 0 to 2;
- \quadquad
- R^{1} es alquilo C_{1}-C_{10}, haloalquilo C_{1}-C_{10}, -C(O)R^{14}, -CO_{2}R^{14} o -C(O)NR^{15}R^{16},R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -C (O) R 14, -CO 2 R 14 or -C (O) NR 15 R 16,
- \quadquad
- R^{14} es hidrógeno o alquilo C_{1}-C_{10};R 14 is hydrogen or alkyl C 1 -C 10;
- \quadquad
- R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10};R 15 and R 16 are each independently hydrogen or C 1 -C 10 alkyl;
- \quadquad
- R^{2} es fenilo.R2 is phenyl.
- \quadquad
- R^{12} es hidrógeno o alquilo C_{1}-C_{10}; y el subíndice m es un número entero de 0 a 2;R 12 is hydrogen or alkyl C 1 -C 10; and the subscript m is a number integer from 0 to 2;
- \quadquad
- R^{1} es alquilo C_{1}-C_{10}, haloalquilo C_{1}-C_{10}, -C(O)R^{14}, -CO_{2}R^{14} o -C(O)NR^{15}R^{16},R 1 is C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, -C (O) R 14, -CO 2 R 14 or -C (O) NR 15 R 16,
- \quadquad
- R^{14} es hidrógeno o alquilo C_{1}-C_{10};R 14 is hydrogen or alkyl C 1 -C 10;
- \quadquad
- R^{15} y R^{16} son cada uno independientemente hidrógeno o alquilo C_{1}-C_{10};R 15 and R 16 are each independently hydrogen or C 1 -C 10 alkyl;
- \quadquad
- R^{2} es fenilo para modular una condición asociada con un trastorno metabólico o inflamatorio en un anfitrión.R2 is phenyl to modulate a condition associated with a metabolic or inflammatory disorder in a host.
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2002
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CA2318731C (en) | 2012-05-29 |
AU2117699A (en) | 1999-08-16 |
US7439242B2 (en) | 2008-10-21 |
DE69939864D1 (en) | 2008-12-18 |
WO1999038845A1 (en) | 1999-08-05 |
JP2002501945A (en) | 2002-01-22 |
US6200995B1 (en) | 2001-03-13 |
CA2318731A1 (en) | 1999-08-05 |
AU759255B2 (en) | 2003-04-10 |
US20010027200A1 (en) | 2001-10-04 |
ATE413386T1 (en) | 2008-11-15 |
EP1053227A1 (en) | 2000-11-22 |
US20030088103A1 (en) | 2003-05-08 |
US6620827B2 (en) | 2003-09-16 |
JP4253126B2 (en) | 2009-04-08 |
EP1053227B1 (en) | 2008-11-05 |
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